Pyridine, quinoline, and isoquinoline N-oxides as kinase inhibitors

ABSTRACT

This invention relates to urea compounds containing a pyridine, quinoline, or isoquinoline functionality which is oxidized at the nitrogen heteroatom and which are useful in the treatment of (i) raf mediated diseases, for example, cancer, (ii) p38 mediated diseases such as inflammation and osteoporosis, and (iii) VEGF mediated diseases such as angiogenesis disorders.

FIELD OF THE INVENTION

[0001] This invention relates to urea compounds containing a pyridine,quinoline, or isoquinoline functionality, which are useful in thetreatment of:

[0002] (i) raf mediated diseases, for example, cancer,

[0003] (ii) p38 mediated diseases such as inflammation and osteoporosis,and

[0004] (iii) VEGF mediated diseases such as angiogenesis disorders.

BACKGROUND OF THE INVENTION

[0005] Activation of the Ras signal transduction pathway indicates acascade of events that have a profound impact on cellular proliferation,differentiation, and transformation. Raf kinase, a downstream effectorof Ras, is a key mediator of these signals from cell surface receptorsto the cell nucleus (Lowy, D. R.; Willumsen, B. M. Ann. Rev. Biochem.1993, 62, 851; Bos, J. L. Cancer Res. 1989, 49, 4682). It has been shownthat inhibiting the effect of active ras by inhibiting the raf kinasesignaling pathway by administration of deactivating antibodies to rafkinase or by co-expression of dominant negative raf kinase or dominantnegative MEK, the substrate of raf kinase, leads to the reversion oftransformed cells to the normal growth phenotype (see: Daum et al.Trends Biochem. Sci. 1994, 19, 474-80; Fridman et al. J. Biol. Chem.1994, 269, 30105-8. Kolch et al. (Nature 1991, 349, 426-28) have furtherindicated that inhibition of raf expression by antisense RNA blocks cellproliferation in membrane-associated oncogenes. Similarly, inhibition ofraf kinase (by antisense oligodeoxynucleotides) has been correlated invitro and in vivo with inhibition of the growth of a variety of humantumor types (Monia et al., Nat. Med. 1996, 2, 668-75). Thus, smallmolecule inhibitors of Raf kinase activity are important agents for thetreatment of cancer (Naumann, U.; Eisenmann-Tappe, I.; Rapp, U. R.Recent Results Cancer Res. 1997, 143, 237; Monia, B. P.; Johnston, J.F.; Geiger, T.; Muller, M.; Fabbro, D. Nature Medicine 1996, 2, 668).

[0006] Inhibition of p38 has been shown to inhibit both cytokineproduction (eg., TNFα, IL-1, IL-6, IL-8) and proteolytic enzymeproduction (eg., MMP-1, MMP-3) in vitro and/or in vivo. The mitogenactivated protein (MAP) kinase p38 is involved in IL-1 and TNF signalingpathways (Lee, J. C.; Laydon, J. T.; McDonnell, P. C.; Gallagher, T. F.;Kumar, S.; Green, D.; McNulty, D.; Blumenthal, M. J.; Heys, J. R.;Landvatter, S. W.; Stricker, J. E.; McLaughlin, M. M.; Siemens, I. R.;Fisher, S. M.; Livi, G. P.; White, J. R.; Adams, J. L.; Yound, P. R.Nature 1994, 372, 739).

[0007] Clinical studies have linked TNFα production and/or signaling toa number of diseases including rheumatoid arthritis (Maini. J. RoyalColl. Physicians London 1996, 30, 344). In addition, excessive levels ofTNFα have been implicated in a wide variety of inflammatory and/orimmunomodulatory diseases, including acute rheumatic fever (Yegin et al.Lancet 1997, 349, 170), bone resorption (Pacifici et al. J. Clin.Endocrinol. Metabol. 1997, 82, 29), postmenopausal osteoperosis(Pacifici et al. J. Bone Mineral Res. 1996, 11, 1043), sepsis (Blackwellet al. Br. J. Anaesth. 1996, 77, 110), gram negative sepsis (Debets etal. Prog. Clin. Biol. Res. 1989, 308, 463), septic shock (Tracey et al.Nature 1987, 330, 662; Girardin et al. New England J. Med. 1988, 319,397), endotoxic shock (Beutler et al. Science 1985, 229, 869; Ashkenasiet al. Proc. Nat'l. Acad. Sci. USA 1991, 88, 10535), toxic shocksyndrome, (Saha et al. J. Immunol. 1996, 157, 3869; Lina et al. FEMSImmunol. Med. Microbiol. 1996, 13, 81), systemic inflammatory responsesyndrome (Anon. Crit. Care Med. 1992, 20, 864), inflammatory boweldiseases (Stokkers et al. J. Inflamm. 1995-6, 47, 97) including Crohn'sdisease (van Deventer et al. Aliment. Pharmacol. Therapeu. 1996, 10(Suppl. 2), 107; van Dullemen et al. Gastroenterology 1995, 109, 129)and ulcerative colitis (Masuda et al. J. Clin. Lab. Immunol. 1995, 46,111), Jarisch-Herxheimer reactions (Fekade et al. New England J. Med.1996, 335, 311), asthma (Amrani et al. Rev. Malad. Respir. 1996, 13,539), adult respiratory distress syndrome (Roten et al. Am. Rev. Respir.Dis. 1991, 143, 590; Suter et al. Am. Rev. Respir. Dis. 1992, 145,1016), acute pulmonary fibrotic diseases (Pan et al. Pathol. Int. 1996,46, 91), pulmonary sarcoidosis (Ishioka et al. Sarcoidosis VasculitisDiffuse Lung Dis. 1996, 13, 139), allergic respiratory diseases (Casaleet al. Am. J. Respir. Cell Mol. Biol. 1996, 15, 35), silicosis (Gossartet al. J. Immunol. 1996, 156, 1540; Vanhee et al. Eur. Respir. J. 1995,8, 834), coal worker's pneumoconiosis (Borm et al. Am. Rev. Respir. Dis.1988, 138, 1589), alveolar injury (Horinouchi et al. Am. J. Respir. CellMol. Biol. 1996, 14, 1044), hepatic failure (Gantner et al. J.Pharmacol. Exp. Therap. 1997, 280, 53), liver disease during acuteinflammation (Kim et al. J. Biol. Chem. 1997, 272, 1402), severealcoholic hepatitis (Bird et al. Ann. Intern. Med. 1990, 112, 917),malaria (Grau et al. Immunol. Rev. 1989, 112, 49; Taveme et al.Parasitol. Today 1996, 12, 290) including Plasmodium falciparum malaria(Perlmann et al. Infect. Immunit. 1997, 65, 116) and cerebral malaria(Rudin et al. Am. J. Pathol. 1997, 150, 257), non-insulin-dependentdiabetes mellitus (NIDDM; Stephens et al. J. Biol. Chem. 1997, 272, 971;Ofei et al. Diabetes 1996, 45, 881), congestive heart failure (Doyama etal. Int. J. Cardiol. 1996, 54, 217; McMurray et al. Br. Heart J. 1991,66, 356), damage following heart disease (Malkiel et al. Mol. Med. Today1996, 2, 336), atherosclerosis (Parums et al. J. Pathol. 1996, 179,A46), Alzheimer's disease (Fagarasan et al. Brain Res. 1996, 723, 231;Aisen et al. Gerontology 1997, 43, 143), acute encephalitis (Ichiyama etal. J. Neurol. 1996, 243, 457), brain injury (Cannon et al. Crit. CareMed. 1992, 20, 1414; Hansbrough et al. Surg. Clin. N. Am. 1987, 67, 69;Marano et al. Surg. Gynecol. Obstetr. 1990, 170, 32), multiple sclerosis(M.S.; Coyle. Adv. Neuroimmunol. 1996, 6, 143; Matusevicius et al. J.Neuroimmunol. 1996, 66, 115) including demyelation and oligiodendrocyteloss in multiple sclerosis (Brosnan et al. Brain Pathol. 1996, 6, 243),advanced cancer (MucWierzgon et al. J. Biol. Regulators HomeostaticAgents 1996, 10, 25), lymphoid malignancies (Levy et al. Crit. Rev.Immunol. 1996, 16, 31), pancreatitis (Exley et al. Gut 1992, 33, 1126)including systemic complications in acute pancreatitis (McKay et al. Br.J. Surg. 1996, 83, 919), impaired wound healing in infectioninflammation and cancer (Buck et al. Am. J. Pathol. 1996, 149, 195),myelodysplastic syndromes (Raza et al. Int. J. Hematol. 1996, 63, 265),systemic lupus erythematosus (Maury et al. Arthritis Rheum. 1989, 32,146), biliary cirrhosis (Miller et al. Am. J. Gasteroenterolog. 1992,87, 465), bowel necrosis (Sun et al. J. Clin. Invest. 1988, 81, 1328),psoriasis (Christophers. Austr. J. Dermatol. 1996, 37, S4), radiationinjury (Redlich et al. J. Immunol. 1996, 157, 1705), and toxicityfollowing administration of monoclonal antibodies such as OKT3 (Brod etal. Neurology 1996, 46, 1633). TNFα levels have also been related tohost-versus-graft reactions (Piguet et al. Immunol. Ser. 1992, 56, 409)including ischemia reperfusion injury (Colletti et al. J. Clin. Invest.1989, 85, 1333) and allograft rejections including those of the kidney(Maury et al. J. Exp. Med. 1987, 166, 1132), liver (Imagawa et al.Transplantation 1990, 50, 219), heart (Bolling et al. Transplantation1992, 53, 283), and skin (Stevens et al. Transplant. Proc. 1990, 22,1924), lung allograft rejection (Grossman et al. Immunol. Allergy Clin.N. Am. 1989, 9, 153) including chronic lung allograft rejection(obliterative bronchitis; LoCicero et al. J. Thorac. Cardiovasc. Surg.1990, 99, 1059), as well as complications due to total hip replacement(Cirino et al. Life Sci. 1996, 59, 86). TNFα has also been linked toinfectious diseases (review: Beutler et al. Crit. Care Med. 1993, 21,5423; Degre. Biotherapy 1996, 8, 219) including tuberculosis (Rook etal. Med. Malad. Infect. 1996, 26, 904), Helicobacter pylori infectionduring peptic ulcer disease (Beales et al. Gastroenterology 1997, 112,136), Chaga's disease resulting from Trypanosoma cruzi infection(Chandrasekar et al. Biochem. Biophys. Res. Commun. 1996, 223, 365),effects of Shiga-like toxin resulting from E. coli infection (Harel etal. J. Clin. Invest. 1992, 56, 40), the effects of enterotoxin Aresulting from Staphylococcus infection (Fischer et al. J. Immunol.1990, 144, 4663), meningococcal infection (Waage et al. Lancet 1987,355; Ossege et al. J. Neurolog. Sci. 1996, 144, 1), and infections fromBorrelia burgdorferi (Brandt et al. Infect. Immunol. 1990, 58, 983),Treponema pallidum (Chamberlin et al. Infect. Immunol. 1989, 57, 2872),cytomegalovirus (CMV; Geist et al. Am. J. Respir. Cell Mol. Biol. 1997,16, 31), influenza virus (Beutler et al. Clin. Res. 1986, 34, 491 a),Sendai virus (Goldfield et al. Proc. Nat'l. Acad. Sci. USA 1989, 87,1490), Theiler's encephalomyelitis virus (Sierra et al. Immunology 1993,78, 399), and the human immunodeficiency virus (HIV; Poli. Proc. Nat'l.Acad. Sci. USA 1990, 87, 782; Vyakaram et al. AIDS 1990, 4, 21; Badleyet al. J. Exp. Med. 1997, 185, 55).

[0008] A number of diseases are thought to be mediated by excess orundesired matrix-destroying metalloprotease (MMP) activity or by animbalance in the ratio of the MMPs to the tissue inhibitors ofmetalloproteinases (TIMPs). These include osteoarthritis (Woessner etal. J. Biol. Chem. 1984, 259, 3633), rheumatoid arthritis (Mullins etal. Biochim. Biophys. Acta 1983, 695, 117; Woolley et al. ArthritisRheum. 1977, 20, 1231; Gravallese et al. Arthritis Rheum. 1991, 34,1076), septic arthritis (Williams et al. Arthritis Rheum. 1990, 33,533), tumor metastasis (Reich et al. Cancer Res. 1988, 48, 3307;Matrisian et al. Proc. Nat'l. Acad. Sci., USA 1986, 83, 9413),periodontal diseases (Overall et al. J. Periodontal Res. 1987, 22, 81),corneal ulceration (Burns et al. Invest. Opthalmol. Vis. Sci. 1989, 30,1569), proteinuria (Baricos et al. Biochem. J. 1988, 254, 609), coronarythrombosis from atherosclerotic plaque rupture (Henney et al. Proc.Nat'l. Acad. Sci., USA 1991, 88, 8154), aneurysmal aortic disease (Vineet al. Clin. Sci. 1991, 81, 233), birth control (Woessner et al.Steroids 1989, 54, 491), dystrophobic epidermolysis bullosa (Kronbergeret al. J. Invest. Dermatol. 1982, 79, 208), degenerative cartilage lossfollowing traumatic joint injury, osteopenias mediated by MMP activity,tempero mandibular joint disease, and demyelating diseases of thenervous system (Chantry et al. J. Neurochem. 1988, 50, 688).

[0009] Because inhibition of p38 leads to inhibition of TNFα productionand MMP production, inhibition of mitogen activated protein (MAP) kinasep38 enzyme provides an approach to the treatment of the above listeddiseases including osteoporosis and inflammatory disorders such asrheumatoid arthritis and COPD (Badger, A. M.; Bradbeer, J. N.; Votta,B.; Lee, J. C.; Adams, J. L.; Griswold, D. E. J. Pharm. Exper. Ther.1996, 279, 1453).

[0010] Vasculogenesis involves the de novo formation of blood vesselsfrom endothelial cell precursors or angioblasts. The first vascularstructures in the embryo are formed by vasculogenesis. Angiogenesisinvolves the development of capillaries from existing blood vessels, andis the principle mechanism by which organs, such as the brain and thekidney are vascularized. While vasculogenesis is restricted to embryonicdevelopment, angiogenesis can occur in the adult, for example duringpregnancy, the female cycle, or wound healing.

[0011] One major regulator of angiogenesis and vasculogenesis in bothembryonic development and some angiogenic-dependent diseases is vascularendothelial growth factor (VEGF; also called vascular permeabilityfactor, VPF). VEGF represents a family of isoforms of mitogens existingin homodimeric forms, due to alternative RNA splicing. The VEGF isoformsare highly specific for vascular endothelial cells (for reviews, see:Farrara et al. Endocr. Rev. 1992, 13, 18; Neufield et al. FASEB J. 1999,13, 9). VEGF expression is induced by hypoxia (Shweiki et al. Nature1992, 359, 843), as well as by a variety of cytokines and growthfactors, such as interleukin-1, interleukin-6, epidermal growth factorand transforming growth factor.

[0012] To date, VEGF and the VEGF family members have been reported tobind to one or more of three transmembrane receptor tyrosine kinases(Mustonen et al. J. Cell Biol., 1995, 129, 895), VEGF receptor-1 (alsoknown as flt-1 (fms-like tyrosine kinase-1)), VEGFR-2 (also known askinase insert domain containing receptor (KDR); the murine analogue ofKDR is known as fetal liver kinase-1 (flk-1)), and VEGFR-3 (also knownas flt-4). KDR and flt-1 have been shown to have different signaltransduction properties (Waltenberger et al. J. Biol. Chem. 1994, 269,26988); Park et al. Oncogene 1995, 10, 135). Thus, KDR undergoes strongligand-dependant tyrosine phosphorylation in intact cells, whereas flt-idisplays a weak response. Thus, binding to KDR is a critical requirementfor induction of the full spectrum of VEGF-mediated biologicalresponses.

[0013] In vivo, VEGF plays a central role in vasculogenesis, and inducesangiogenesis and permeabilization of blood vessels. Deregulated VEGFexpression contributes to the development of a number of diseases thatare characterized by abnormal angiogenesis and/or hyperpermeabilityprocesses. Regulation of the VEGF-mediated signal transduction cascadewill therefore provide a useful mode for control of abnormalangiogenesis and/or hyperpermeability processes.

[0014] Angiogenesis is regarded as an absolute prerequisite for growthof tumors beyond about 1-2 mm. Oxygen and nutrients may be supplied tocells in tumors smaller than this limit through diffusion. However,every tumor is dependent on angiogenesis for continued growth after ithas reached a certain size. Tumorigenic cells within hypoxic regions oftumors respond by stimulation of VEGF production, which triggersactivation of quiescent endothelial cells to stimulate new blood vesselformation. (Shweiki et al. Proc. Nat'l. Acad. Sci., 1995, 92, 768). Inaddition, VEGF production in tumor regions where there is noangiogenesis may proceed through the ras signal transduction pathway(Grugel et al. J. Biol. Chem., 1995, 270, 25915; Rak et al. Cancer Res.1995, 55, 4575). In situ hybridization studies have demonstrated VEGFmRNA is strongly upregulated in a wide variety of human tumors,including lung (Mattern et al. Br. J. Cancer 1996, 73, 931), thyroid(Viglietto et al. Oncogene 1995, 11, 1569), breast (Brown et al. HumanPathol. 1995, 26, 86), gastrointestional tract (Brown et al. Cancer Res.1993, 53, 4727; Suzuki et al. Cancer Res. 1996, 56, 3004), kidney andbladder (Brown et al. Am. J. Pathol. 1993, 1431,1255), ovary (Olson etal. Cancer Res. 1994, 54, 1255), and cervical (Guidi et al. J. Nat'lCancer Inst. 1995, 87, 12137) carcinomas, as well as angiosacroma(Hashimoto et al. Lab. Invest. 1995, 73, 859) and several intracranialtumors (Plate et al. Nature 1992, 359, 845; Phillips et al. Int. J.Oncol. 1993, 2, 913; Berkman et al. J. Clin. Invest., 1993, 91, 153).Neutralizing monoclonal antibodies to KDR have been shown to beefficacious in blocking tumor angiogenesis (Kim et al. Nature 1993, 362,841; Rockwell et al. Mol. Cell. Differ. 1995, 3, 315).

[0015] Overexpression of VEGF, for example under conditions of extremehypoxia, can lead to intraocular angiogenesis, resulting inhyperproliferation of blood vessels, leading eventually to blindness.Such a cascade of events has been observed for a number ofretinopathies, including diabetic retinopathy, ischemic retinal-veinocclusion, retinopathy of prematurity (Aiello et al. New Engl. J. Med.1994, 331, 1480; Peer et al. Lab. Invest. 1995, 72, 638), andage-related macular degeneration (AMD; see, Lopez et al. Invest.Opththalmol. Vis. Sci. 1996, 37, 855).

[0016] In rheumatoid arthritis (RA), the in-growth of vascular pannusmay be mediated by production of angiogenic factors. Levels ofimmunoreactive VEGF are high in the synovial fluid of RA patients, whileVEGF levels are low in the synovial fluid of patients with other formsof arthritis of with degenerative joint disease (Koch et al. J. Immunol.1994, 152, 4149). The angiogenesis inhibitor AGM-170 has been shown toprevent neovascularization of the joint in the rat collagen arthritismodel (Peacock et al. J. Exper. Med. 1992, 175, 1135).

[0017] Increased VEGF expression has also been shown in psoriatic skin,as well as bullous disorders associated with subepidermal blisterformation, such as bullous pemphigoid, erythema multiforme, anddermatitis herpetiformis (Brown et al. J. Invest. Dermatol. 1995, 104,744).

[0018] Because inhibition of KDR leads to inhibition of VEGF-mediatedangiogenesis and permeabilization, KDR inhibitors will be useful intreatment of diseases characterized by abnormal angiogenesis and/orhyperpermeability processes, including the above listed diseases.

SUMMARY OF THE INVENTION

[0019] The current invention provides a kinase inhibitor class of noveldiarylureas of formula (I) below, pharmaceutical compositions whichcontain them and methods for their use. The compounds of the presentinvention are useful as therapeutic compounds for the treatment andprevention of cancer, inflammation, and osteoporosis.

[0020] As inhibitors of raf kinase, these compounds are useful in thetreatment of tumors and/or cancerous growth mediated by raf kinase. Inparticular, the compounds are useful in the treatment of human or animalsolid cancers, e.g., murine cancer, carcinomas (e.g., of the lungs,pancreas, thyroid, bladder or colon), myeloid disorders (e.g., mycloidleukemia) or adenomas (e.g., villous colon adenoma).

[0021] As inhibitors of p38 mediated events, these compounds are usefulin treating cytokine mediated disease states and protease mediateddisease states in humans or mammals, wherein the cytokine and proteaseare those whose production is affected by p38. Accordingly, thesecompounds are useful therapeutic agents for such acute and chronicinflammatory and/or immunomodulatory diseases as rheumatoid arthritisand osteoperosis.

[0022] As inhibitors of VEGF receptor kinases, these compounds areuseful in the treatment of diseases where angiogenesis andneovascularization are part of the etiology.

[0023] The present invention, therefore, also provides:

[0024] (i) methods for the treatment of raf-mediated disease states inhumans or mammals, such as cancer, wherein a compound of formula I isadministered, or a salt, prodrug or isolated stereoisomer thereof,

[0025] (ii) methods for the treatment of p38-mediated disease states inhumans or mammals, such as inflammation, wherein a compound of formula Iis administered, or a salt, prodrug or isolated stereoisomer thereof,

[0026] (iii) methods for the treatment of VEGF-mediated disease statesin humans or mammals, such as diabetic retinopathy, wherein a compoundof formula I is administered, or a salt, prodrug or isolatedstereoisomer thereof.

[0027] The invention relates to a compound of formula (I) or a salt,prodrug or isolated stereoisomer thereof (collectively referred toherein as “compounds of this invention”),

M-L-B-NH—C(O)—NH-A  I

[0028] wherein A is selected from the group consisting of

[0029] (i) phenyl, optionally substituted with 1-3 substituentsindependently selected from the group consisting of R¹, OR¹, NR¹R²,S(O)_(q)R₁, SO₂NR¹R², NR¹SO₂R², COR¹, COOR¹, CONR¹R², NR¹C(O)R²,halogen, cyano, and nitro;

[0030] (ii) naphthyl, optionally substituted with 1-3 substituentsindependently selected from the group consisting of R¹, OR¹, NR¹R²,S(O)_(q)R₁, SO₂NR¹R², NR¹SO₂R¹, COR¹, COOR¹, CONR¹R², NR¹C(O)R²,halogen, cyano, and nitro;

[0031] (iii) 5 and 6 membered monocyclic heteroaryl, having 1-3heteroatoms independently selected from the group consisting of O, N andS, optionally substituted with 1-3 substituents independently selectedfrom the group consisting of R¹, OR¹, NR¹R², S(O)_(q)R₁, SO₂NR¹R²,NR¹SO₂R²,COR¹, COOR¹, CONR¹R², NR¹COR², halogen, cyano, and nitro; and

[0032] (iv) 8-10 membered bicyclic heteroaryl, having 1-6 heteroatomsindependently selected from the group consisting of O, N and S,optionally substituted with 1-3 substituents independently selected fromthe group consisting of R¹, OR¹, NR¹R², S(O)_(q)R₁, SO₂NR¹R², NR¹SO₂R²,COR¹, COOR¹, CONR¹R², NR¹COR², halogen, cyano, and nitro.

[0033] B is selected from the group consisting of

[0034] (i) phenylene, optionally substituted with 1-3 substituentsindependently selected from the group consisting of C₁-C₅ linear orbranched alkyl, C₁-C₅ linear or branched haloalkyl, C₁-C₃ alkoxy,hydroxy, amino, C₁-C₃ alkylamino, C₁-C₃ dialkylamino, halogen, cyano,and nitro;

[0035] (ii) naphthylene, optionally substituted with 1-3 substituentsindependently selected from the group consisting of C₁-C₅ linear orbranched alkyl, C₁-C₅ linear or branched haloalkyl, C₁-C₃ alkoxy,hydroxy, amino, C₁-C₃ alkylamino, C₁-C₃ dialkylamino, halogen, cyano,and nitro;

[0036] (iii) 5 and 6 membered monocyclic heteroaryl-ene, having 1-3heteroatoms independently selected from the group consisting of O, N andS, optionally substituted with 1-3 substituents independently selectedfrom the group consisting of C₁-C₅ linear or branched alkyl, C₁-C₅linear or branched haloalkyl, C₁-C₃ alkoxy, hydroxy, amino, C₁-C₃alkylamino, C₁-C₃ dialkylamino, halogen, cyano, and nitro; and

[0037] (iv) 8-10 membered bicyclic heteroaryl-ene, having 1-6heteroatoms independently selected from the group consisting of O, N andS, optionally substituted with 1-3 substituents independently selectedfrom the group consisting of C₁-C₅ linear or branched alkyl, C₁-C₅linear or branched haloalkyl, C₁-C₃ alkoxy, hydroxy, amino, C₁-C₃alkylamino, C₁-C₃ dialkylamino, halogen, cyano, and nitro.

[0038] L is selected from the group consisting of:

[0039] (a) —(CH₂)_(m)—O—(CH₂)_(l)—,

[0040] (b) —(CH₂)_(m)—(CH₂)_(l)—,

[0041] (c) —(CH₂)_(m)—C(O)—(CH₂)_(l)—,

[0042] (d) —(CH₂)_(m)—NR^(3a)—(CH₂)_(l)—,

[0043] (e) —(CH₂)_(m)—NR^(3a)—C(O)—(CH₂)_(l)—,

[0044] (f) —(CH₂)_(m)—S—(CH₂)_(l)—,

[0045] (g) —(CH₂)_(m)—C(O)NR^(3a)—(CH₂)₁—,

[0046] (h) —(CH₂)_(m)—CF₂—(CH₂)_(l)—,

[0047] (i) —(CH₂)_(m)—CCl₂—(CH₂)_(l)—,

[0048] (j) —(CH₂)_(m)—CHF—(CH₂)_(l)—, and

[0049] (k) —(CH₂)_(m)—CR^(3a)(OH)—(CH₂)_(l)—;

[0050] (l) —(CH₂)_(m)—C≡C—(CH₂)_(l)—;

[0051] (m) —(CH₂)_(m)—C=C—(CH₂)_(l)—;

[0052] (n) a single bond; and

[0053] (o) —(CH₂)_(m)—CR^(3a)R^(3b)—(CH₂)_(l)—;

[0054] wherein m and l are integers independently selected from 0-4.

[0055] M is selected from the group consisting of

[0056] a) pyridine-1-oxide substituted 1 to 3 times by a substituentselected from the group consisting of —C(O)NR⁴R⁵, —C(NR⁴)R⁵, —C(O)R⁴,—SO₂R⁴, and —SO₂NR⁴R⁵; which is optionally additionally substituted byZ_(r);

[0057] b) quinoline-1-oxide, which is optionally substituted by Z_(n);and

[0058] c) isoquinoline-1-oxide, which is optionally substituted by Z_(n)

[0059] wherein

[0060] r is 0-2,

[0061] n is 0-3, and

[0062] each Z is independently selected from the group consisting of R⁴,halogen, cyano, —CO₂R⁴, —C(O)R⁴, —C(O)NR⁴R⁵, —NO₂, —OR⁴—, —NR⁴R⁵,—NR⁴C(O)OR⁵, —NR⁴C(O)R⁵, —S(O)_(p)R⁴, and —SO₂NR⁴R⁵.

[0063] Each R¹, R², R⁴ and R⁵ are independently selected from the groupconsisting of:

[0064] (a) hydrogen,

[0065] (b) C₁-C₅ linear, branched, or cyclic alkyl,

[0066] (c) phenyl,

[0067] (d) 5-6 membered monocyclic heteroaryl heteroaryl having 1-4heteroatoms selected from the group consisting of O, N and S or 8-10membered bicyclic heteroaryl having 1-6 heteroatoms selected from thegroup consisting of O, N and S,

[0068] (e) C₁-C₃ alkyl-phenyl,

[0069] (f) C₁-C₃ alkyl heteroaryl having 1-4 heteroatoms selected fromthe group consisting of O, N and S, said heteroaryl including 5-6membered monocyclic and 8-10 membered bicyclic heteroaryl, and

[0070] (g) up to per-halo substituted C₁-C₅ linear or branched alkyl.

[0071] R^(3a) and R^(3b) are independently, hydrogen or C₁-C₅ linear orbranched alkyl.

[0072] Each R¹, R², R⁴ and R⁵, when not hydrogen or perhalo substitutedC₁-C₅ linear or branched alkyl, are optionally substituted with 1-3substituents independently selected from the group consisting of C₁-C₅linear or branched alkyl, up to perhalo substituted C₁-C₅ linear orbranched alkyl, C₁-C₃ alkoxy, hydroxy, amino, C₁-C₃ alkylamino, C₁-C₆dialkylamino, halogen, cyano, and nitro;

[0073] and p and q are integers each independently selected from 0, 1,or 2.

[0074] The compounds of this invention do not include compounds ofFormula II below, or salts, prodrugs or isolated stereoisomers thereof,

[0075] wherein, Y is OR¹ or NHR², Hal is chlorine or bromine, R¹ is H orC₁-C₆ alkyl R² is H, OH, CH₃ or CH₂OH, X¹ to X⁷ are each, independently,H, OH or O(CO)C₁-C₄ alkyl.

[0076] For compounds of formula II, the C(O)Y substitutedpyridine-1-oxide conforms to M of formula I, the X⁴ to X⁷ substitutedphenyl conforms to B of formula I, the oxygen bridge, —O—, conforms to Lof formula I and the X¹ to X³ substituted3-trifluoromethyl-4-halo-phenyl conforms to A of formula I.

[0077] It is understood that the term “pyridine-1-oxide” used throughoutthis document includes those structures referred to in the art as1-oxo-pyridine and 1-hydroxy-pyridine. For example, ChemInnovationSoftware, Inc. Nomenclator™ v. 3.01 identifies compounds of formula IIwhere Y=NHCH₃, Hal=Cl and X¹-X⁷=H, drawn in ChemDraw, asN-[4-chloro-3-(trifluoromethyl)phenyl]({4-[1-hydroxy-2-(N-methylcarbamoyl)(4-pyridyloxy)]phenyl}amino)carboxamide.The same remark applies to the quinoline-1-oxides and theisoquinoline-1-oxides.

[0078] Suitable substituted and unsubstituted heteroaryl groups for thecompounds of this invention, such as those for A and B of formula I,include, but are not limited to monocyclic heteroaryl groups such as 2-or 3-furyl, 2- or 3-thienyl, 2- or 4-triazinyl, 1-, 2- or 3-pyrrolyl,1-, 2-, 4- or 5-imidazolyl, 1-, 3-, 4- or 5-pyrazolyl, 2-, 4- or5-oxazolyl, 3-, 4- or 5-isoxazolyl, 2-, 4- or 5-thiazolyl, 3-, 4- or5-isothiazolyl, 2-, 3- or 4-pyridyl, 2-, 4-, 5- or 6-pyrimidinyl,1,2,3-triazol-1-, -4- or -5-yl, 1,2,4-triazol-1-, -3- or -5-yl, 1- or5-tetrazolyl, 1,2,3-oxadiazol-4- or -5-yl, 1,2,4-oxadiazol-3- or -5-yl,1,3,4-thiadiazol-2- or -5-yl, 1,2,4-oxadiazol-3- or 5-yl,1,3,4-thiadiazol-2- or -5-yl, 1,3,4-thiadiazol-3- or -5-yl,1,2,3-thiadiazol-4- or -5-yl, 3- or 4-pyridazinyl and 2-,3-pyrazinyl.

[0079] Suitable substituted and unsubstituted heteroaryl groups for thecompounds of this invention, such as those for A and B of formula I,include, but are not limited to bicyclic heteroaryl groups. Examples ofbicyclic heteroaryl rings include 5-5,5-6, and 6-6 fused bicycles, whereone of the rings is one of the above heteroaryl rings and the secondring is either benzene or another heteroaryl ring, for example 2-, 3-,4-, 5-, 6- or 7-benzofuryl, 2-, 3-, 4-, 5-, 6- or 7-benzothienyl, 1-,2-, 3-, 4-, 5-, 6- or 7-indolyl, 1-, 2-, 3-, 4-, 5-, 6- or 7-isoindolyl,1-, 2-, 4- or 5-benzimidazolyl, 1-, 3-, 4-, 5-, 6- or 7-indazolyl(benzopyrazolyl), 2-, 4-, 5-, 6- or 7-benzoxazolyl, 3-, 4-, 5-6- or7-benzisoxazolyl, 1-, 3-, 4-, 5-, 6- or 7-benzothiazolyl, 2-, 4-, 5-, 6-or 7-benzisothiazolyl, 2-, 4-, 5-, 6- or 7-benz-1,3-oxadiazolyl, 2-, 3-,4-, 5-, 6-, 7- or 8-quinolinyl, 1-, 3-, 4-, 5-, 6-, 7-, 8-isoquinolinyl,or 2-, 4-, 5-, 6-, 7- or 8-quinazolinyl.

[0080] More specifically, the substituted heteroaryl groups can be, forexample, 5-methyl-2-thienyl, 4-methyl-2-thienyl, 1-methyl-3-pyrryl,1-methyl-3-pyrazolyl, 5-methyl-2-thiazolyl,5-methyl-1,2,4-thiadiazol-2-yl and others.

[0081] Suitable linear alkyl groups and alkyl portions of groups, e.g.,alkoxy, alkylphenyl and alkylbeteroaryl etc. throughout include methyl,ethyl, propyl, butyl, pentyl, etc. Suitable branched alkyl groupsinclude all branched isomers such as isopropyl, isobutyl, sec-butyl,tert-butyl, etc.

[0082] The term “up to perhalo substituted linear and branched alkyl,”includes alkyl groups having one alkyl hydrogen replaced with halogen,alkyl groups wherein all hydrogens are replaced with halogen, alkylgroups wherein more than one but less than all hydrogens are replaced byhalogen and alkyl groups having alkyl hydrogens replaced by halogen andother substituents.

[0083] Suitable halogen groups include F, Cl, Br, and/or I, from one toper-substitution (i.e. all H atoms on a group replaced by a halogenatom) being possible where an alkyl group is substituted by halogen,mixed substitution of halogen atom types also being possible on a givenmoiety. Preferred halogens are Cl, Br and F.

[0084] The term “cycloalkyl”, as used herein, refers to cyclicstructures having 3-8 members in the ring such as cyclopropyl,cyclobutyl and cyclopentyl and cyclic structures having 3-8 members withalkyl substituents such that, for example, “C₃ cycloalkyl” includesmethyl substituted cyclopropyl groups.

[0085] The term “saturated carbocyclic moieties” defines only the cyclicstructure, i.e. cyclopentyl, cyclohexyl, etc. Any alkyl substitution onthese cyclic structures is specifically identified.

[0086] Particularly preferred compounds of this invention are defined byformula I, wherein:

[0087] A is selected from phenyl, naphthyl, furyl, isoindolyl,oxadiazolyl, oxazolyl, isooxazolyl, indolyl, indazolyl, benzothiazolyl,benzimidazolyl, benzoxazolyl, pyrazolyl, pyridinyl, pyrimidinyl,pyrrolyl, quinolinyl, isoquinolinyl, tetrazolyl, thiadiazolyl, thiazolyland thienyl,

[0088] B is selected from phenylene, naphthylene, thienylene, furylene,pyridine-ene, quinoline-ene, isoquinoline-ene, indole-ene,

[0089] L is selected from —CH₂O—, —OCH₂—, —O—, a single bond, —CH₂—,—NH—, —N(CH₃)—, N(CH₃)CH₂—, —NC₂H₄—, —C(O)—, —NHCH₂—, —N(CH₃)C(O)—,—NHC(O)—, —CH₂N(CH₃)—, —C(O)NH—, —CH₂S—, —SCH₂—, —S—, —C(O)NCH₃—,—CH₂C(O)N(CH₃)—, —C(O)N(CH₃)CH₂—, —CF₂—, —CCl₂—, —CHF— and —CH(OH)—, and

[0090] M is defined as above.

[0091] Particularly preferred substituents for B include methyl,trifluoromethyl, ethyl, n-propyl, n-butyl, n-pentyl, isopropyl,tert-butyl, sec-butyl, methylethyl, methylpropyl, cyclopropyl,cyclobutyl, cyclopentyl, methoxy, ethoxy, propoxy, Cl, Br and F, cyano,nitro, hydroxy, amino, methylamino, dimethylamino, ethylamino anddiethylamino, Preferred substituents for A include methyl,trifluoromethyl, ethyl, n-propyl, n-butyl, n-pentyl, i-propyl, t-butyl,methylethyl, methylpropyl, cyclopropyl, cyclobutyl, cyclopentyl,methoxy, methyl sulfonyl, ethoxy, propoxy, butyoxy, pentoxy, phenoxy,pyridyloxy, Cl, Br, F, cyano, nitro, hydroxy, amino, methylamino,dimethylamino, ethylamino and diethylamino. Preferred substituents for Afurther include substituted or unsubstituted phenyl, pyridyl,pyrimidinyl, quinolinyl, isoquinolinyl, isoindolyl, pyrazolyl,pyridazinyl, pyrrolyl, imidazolyl, indazolyl, thienyl, furyl,isoxazolyl, isothiazolyl, benzothiazolyl, benzyl, and pyridylmethyl.

[0092] Preferred substituents for A also include:

[0093] NH(C₁-C₅ alkyl, phenyl or pyridinyl), such as aminophenyl;

[0094] N(C₁-C₅ alkyl)(C₁-C₅ alkyl, phenyl or pyridinyl), such asdiethylamino and dimethyl amino;

[0095] S(O)₂ (C₁-C₅ alkyl); such as methylsulfonyl;

[0096] SO₂NH(C₁-C₅ alkyl);

[0097] SO₂N(C₁-C₅ alkyl)(C₁-C₅ alkyl);

[0098] NHSO₂(C₁-C₅ alkyl);

[0099] N(C₁-C₃ alkyl) SO₂(C₁-C₅ alkyl);

[0100] CO(C₁-C₆ alkyl, phenyl or pyridinyl);

[0101] COO(C₁-C₆ alkyl, phenyl or pyridinyl), such as C(O)OCH₃,—C(O)OCH₂CH₃, —

[0102] C(O)OCH₂CH₂CH₃;

[0103] COOH;

[0104] CONH₂ (carbamoyl);

[0105] CONH(C₁-C₆ alkyl, phenyl or pyridinyl), such as N-methylethylcarbamoyl, N-methyl carbamoyl, N-ethylcarbamoyl, N-dimethylamino ethylcarbamoyl;

[0106] CON(C₁-C₆ alkyl, phenyl or pyridinyl)(C₁-C₆ alkyl, phenyl orpyridinyl), such as N-dimethyl carbamoyl;

[0107] NHCO(C₁-C₅ alkyl, phenyl or pyridinyl) and

[0108] N(C₁-C₅ alkyl)CO(C₁-C₅ alkyl); each of the above substituents areoptionally partially or fully halogenated, such as difluoromethylsulfonyl and trifluoromethyl sulfonyl.

[0109] An embodiment of this invention includes compounds of thisinvention wherein in formula I, A, and B are one of the followingcombinations and M is as defined above:

[0110] A=phenyl, B=phenylene,

[0111] A=phenyl, B=pyridinyl-ene,

[0112] A=phenyl, B=naphthylene,

[0113] A=phenyl, B=quinolinyl-ene,

[0114] A=phenyl, B=isoquinolinyl-ene,

[0115] A=pyridinyl, B=phenylene,

[0116] A=pyridinyl, B=pyridinyl-ene,

[0117] A=pyridinyl, B=naphthylene,

[0118] A=pyridinyl, B=quinolinyl-ene,

[0119] A=pyridinyl, B=isoquinolinyl-ene,

[0120] A=naphthyl, B=phenylene,

[0121] A=naphthyl, B=pyridinyl-ene,

[0122] A=naphthyl, B=naphthylene,

[0123] A=naphthyl, B=quinolinyl-ene,

[0124] A=naphthyl, B=isoquinolinyl-ene,

[0125] A=isoquinolinyl, B=phenylene,

[0126] A=isoquinolinyl, B=pyridinyl-ene,

[0127] A=isoquinolinyl, B=naphthylene,

[0128] A=isoquinolinyl, B=quinolinyl-ene

[0129] A=isoquinolinyl, B=isoquinolinyl-ene,

[0130] A=quinolinyl, B=phenylene,

[0131] A=quinolinyl, B=pyridinyl-ene,

[0132] A=quinolinyl, B=naphthylene,

[0133] A=quinolinyl, B=quinolinyl-ene

[0134] A=quinolinyl, B=isoquinolinyl-ene,

[0135] A=pyrazolyl, B=phenylene,

[0136] A=pyrazolyl, B=pyridinyl-ene,

[0137] A=pyrazolyl, B=naphthylene,

[0138] A=pyrazolyl, B=quinolinyl-ene,

[0139] A=pyrazolyl, B=isoquinolinyl-ene,

[0140] A=isoxazolyl, B=phenylene,

[0141] A=isoxazolyl, B=pyridinyl-ene,

[0142] A=isoxazolyl, B=naphthylene,

[0143] A=isoxazolyl, B=quinolinyl-ene,

[0144] A=isoxazolyl, B=isoquinolinyl-ene.

[0145] A=indazolyl, B=phenylene,

[0146] A=indazolyl, B=pyridinyl-ene,

[0147] A=indazolyl, B=naphthylene,

[0148] A=indazolyl, B=quinolinyl-ene and

[0149] A=indazolyl, B=isoquinolinyl-ene.

[0150] The invention further relates to processes and methods ofpreparing the novel compounds of this invention.

[0151] The invention further relates to pharmaceutical compositionscomprising one or more compounds of this invention, or a purifiedstereoisomer, a pharmaceutically acceptable salt, or a prodrug of acompound of formula (I).The invention also relates to compounds per se,of formula I.

[0152] One of ordinary skill in the art will recognize that some of thecompounds of Formula (I) can exist in different geometrical isomericforms. A number of the compounds of Formula I possess asymmetric carbonsand can therefore exist in racemic and optically active forms as well asin the form of racemic or nonracemic mixtures thereof, and in the formof diastereomers and diastereomeric mixtures. All of these compounds,including cis isomers, trans isomers, diastereomic mixtures, racemates,nonracemic mixtures of enantiomers, substantially pure, and pureenantiomers, are considered to be within the scope of the presentinvention and are collectively referred to when reference is made tocompounds of this invention.

[0153] Methods of separation of enantiomeric and diastereomeric mixturesare well known to one skilled in the art. The optical isomers can beobtained by resolution of the racemic mixtures according to conventionalprocesses, for example, by the formation of diastereoisomeric saltsusing an optically active acid or base. Examples of appropriate acidsare tartaric, diacetyltartaric, dibenzoyltartaric, ditoluoyltartaric andcamphorsulfonic acid. Mixtures of diastereoisomers can be separated intotheir individual diastereomers on the basis of their physical chemicaldifferences by methods known to those skilled in the art, for example,by chromatography or fractional crystallization. The optically activebases or acids are liberated from the separated diastereomeric salts. Adifferent process for separation of optical isomers involves the use ofa chiral chromatography column (e.g., chiral HPLC columns) optimallychosen to maximize the separation of the enantiomers. Suitable chiralHPLC columns are manufactured by Diacel, e.g., Chiracel OD and ChiracelOJ. The optically active compounds of Formula (I) can likewise beobtained by utilizing optically active starting materials. The presentinvention encompasses any isolated racemic or optically active form ofcompounds described in Formula I which possess raf, p38, and/or VEGFRinhibitory activity. The term stereoisomer is understood to encompassdiastereoisomers, enantiomers, geometric isomers, etc. Herein,substantially pure enantiomers is intended to mean that no more than 5%w/w of the corresponding opposite enantiomer is present.

[0154] Pharmaceutically acceptable salts of these compounds as well ascommonly used prodrugs of these compounds are also within the scope ofthe invention.

[0155] Salts of this invention are especially the pharmaceuticallyacceptable salts of compounds of formula (I) such as, for example,organic or inorganic acid addition salts of compounds of formula (I).Suitable inorganic acids include but are not limited to halogen acids(such as hydrochloric acid and hydrobromic acid), sulfuric acid, orphosphoric acid. Suitable organic acids include but are not limited tocarboxylic, phosphonic, sulfonic, or sulfamic acids, with examplesincluding acetic acid, propionic acid, octanoic acid, decanoic acid,trifluoroacetic acid, dodecanoic acid, glycolic acid, lactic acid, 2- or3-hydroxybutyric acid, γ-aminobutyric acid (GABA), gluconic acid,glucosemonocarboxylic acid, benzoic acid, salicylic acid, phenylaceticacid and mandelic acid, fumaric acid, succinic acid, adipic acid,pimelic acid, suberic acid, azeiaic acid, malic acid, tartaric acid,citric acid, glucaric acid, galactaric acid, amino acids (such asglutamic acid, aspartic acid, N-methylglycine, acetytaminoacetic acid,N-acetylasparagine or N-acetylcysteine), pyruvic acid, acetoacetic acid,methanesulfonic acid, tri-fluoromethane sulfonic acid, 4-toluenesulfonic acid, benzenesulfonic acid, 1-naphthalenesulfonic acid,2-naphthalenesulfonic acid, phosphoserine, and 2- or 3-glycerophosphoricacid.

[0156] In addition, pharmaceutically acceptable salts include acid saltsof inorganic bases, such as salts containing alkaline cations (e.g., Li⁺Na⁺ or K⁺), alkaline earth cations (e.g., Mg⁺², Ca⁺² or Ba⁺²), theammonium cation, as well as acid salts of organic bases, includingaliphatic and aromatic substituted ammonium, and quaternary ammoniumcations, such as those arising from protonation or peralkylation oftriethylamine, N,N-diethylamine, N,N-dicyclohexylamine, lysine,pyridine, N,N-dimethylaminopyridine (DMAP), 1,4-diazabiclo[2.2.2]octane(DABCO), 1,5-diazabicyclo[4.3.0]non-5-ene (DBN) and1,8-diazabicyclo[5.4.0]undec-7-ene (DBU).

[0157] The formation of prodrugs is well known in the art in order toenhance the properties of the parent compound; such properties includesolubility, absorption, biostability and release time (see“Pharmaceutical Dosage Form and Drug Delivery Systems” (Sixth Edition),edited by Ansel et al., published by Williams & Wilkins, pages 27-29,(1995) which is hereby incorporated by reference). Commonly usedprodrugs of the disclosed oxazolyl-phenyl-2,4-diamino-pyrimidinecompounds are designed to take advantage of the major drugbiotransformation reactions and are also to be considered within thescope of the invention. Major drug biotransformation reactions includeN-dealkylation, O-dealkylation, aliphatic hydroxylation, aromatichydroxylation, N-oxidation, S-oxidation, deamination, hydrolysisreactions, glucuronidation, sulfation and acetylation (see Goodman andGilman's The Pharmacological Basis of Therapeutics (Ninth Edition),editor Molinoff et al., publ. by McGraw-Hill, pages 11-13, (1996), whichis hereby incorporated by reference).

[0158] The invention also relates to methods for treating and preventingdiseases, for example, hyper-proliferative, inflammatory andangiogenesis disorder and osteoporosis in mammals by administering acompound of this invention or a pharmaceutical composition comprisingone or more compounds of this invention.

[0159] An embodiment of the present invention is a method for treatingdiseases in humans and/or other mammals which are mediated by the VEGFinduced signal transduction pathway which comprises administering acompound of this invention to a human or other mammal.

[0160] Another embodiment of this invention is a method for treatingdiseases in humans and/or other mammals which are characterized byabnormal angiogenesis or hyperpermiability processes with a compound ofthis invention to a human or other mammal.

[0161] A compound according to the invention can be administeredsimultaneously with another angiogenesis inhibiting agent to a patientwith such a disorder, in the same formulation or, more typically inseparate formulations and, often, using different administration routes.Administration can also be sequentially, in any order.

[0162] A compound according to the invention can be administered intandem with another angiogenesis inhibiting agent, wherein a compoundaccording to the invention can be administered to a patient once or moreper day for up to 28 consecutive days with the concurrent orintermittent administration of another angiogenesis inhibiting agentover the same total time period The invention also relates to a methodof treating or preventing cancer and other hyperproliferative disordersby administering a compound of this invention or a pharmaceuticalcomposition comprising one or more compounds of this invention,optionally in combination with a cytotoxic agent.

[0163] Optional anti-proliferative agents which can be added to thecomposition include but are not limited to compounds listed on thecancer chemotherapy drug regimens in the 11^(th) Edition of the MerckIndex, (1996), which is hereby incorporated by reference, such asasparaginase, bleomycin, carboplatin, carmustine, chlorambucil,cisplatin, colaspase, cyclophosphamide, cytarabine, dacarbazine,dactinomycin, daunorubicin, doxorubicin (adriamycine), epirubicin,etoposide, 5-fluorouracil, hexamethylmelamine, hydroxyurea, ifosfamide,irinotecan, leucovorin, lomustine, mechlorethamine, 6-mercaptopurine,mesna, methotrexate, mitomycin C, mitoxantrone, prednisolone,prednisone, procarbazine, raloxifen, streptozocin, tamoxifen,thioguanine, topotecan, vinblastine, vincristine, and vindesine.

[0164] Additional cytotoxic agents include oxaliplatin, gemcitabone,gefinitib, taxotere, ara A, ara C, herceptin, BCNU, CCNU, DTIC, andactinomycin D. Other anti-proliferative agents suitable for use with thecomposition of the invention include but are not limited to thosecompounds acknowledged to be used in the treatment of neoplasticdiseases in Goodman and Gilman's The Pharmacological Basis ofTherapeutics (Ninth Edition), editor Molinoff et al., publ. byMcGraw-Hill, pages 1225-1287, (1996), which is hereby incorporated byreference such as aminoglutethimide, L-asparaginase, azathioprine,5-azacytidine cladribine, busulfan, diethylstilbestrol,2′,2′-difluorodeoxycytidine, docetaxel, erythrohydroxynonyladenine,ethinyl estradiol, 5-fluorodeoxyuridine, 5-fluorodeoxyuridinemonophosphate, fludarabine phosphate, fluoxymesterone, flutamide,hydroxyprogesterone caproate, idarubicin, interferon,medroxyprogesterone acetate, megestrol acetate, melphalan, mitotane,paclitaxel, pentostatin, N-phosphonoacetyl-L-aspartate (PALA),plicamycin, semustine, teniposide, testosterone propionate, thiotepa,trimethylmelamine, uridine, and vinorelbine.

[0165] Other anti-proliferative agents suitable for use with thecomposition of the invention include but are not limited to otheranti-cancer agents such as epothilone, irinotecan, raloxifen andtopotecan.

[0166] The invention also relates to a pharmaceutical preparation whichcomprises (1) quantities of (a) a compound according to the invention(b) at least one other cytotoxic or cytostatic agent in amounts whichare jointly effective for treating a cancer, where any component (a) or(b) can also be present in the form of a pharmaceutically acceptablesalt if at least one salt-forming group is present, with (2) one or morepharmaceutically acceptable carrier molecules.

[0167] The present invention provides methods for treating a cancer in amammal, especially a human patient, comprising administering an acompound according to the invention optionally in combination with acytotoxic or cytostatic chemotherapeutic agent including, but notlimited to, DNA topoisomerase I and II inhibitors, DNA intercalators,alkylating agents, microtubule disruptors, hormone and growth factorreceptor agonists or antagonists, other kinase inhibitors andantimetabolites. The methods of the present invention can be used totreat a variety of mammal hyperproliferative disorders as defined inthis specification. The compound according to the invention and thecytotoxic or cytostatic agent are administered to a mammal in quantitieswhich together are therapeutically effective against proliferativediseases. Thus, the compound according to the invention is effective forraf kinase-mediated cancers. However, these compounds are also effectivefor cancers not mediated by raf kinase.

[0168] A compound according to the invention can be administeredsimultaneously with a cytotoxic or cytostatic agent to a patient with acancer, in the same formulation or, more typically in separateformulations and, often, using different administration routes.Administration can also be sequentially, in any order.

[0169] A compound according to the invention can be administered intandem with the cytotoxic or cytostatic agent, wherein a compoundaccording to the invention can be administered to a patient once or moreper day for up to 28 consecutive days with the concurrent orintermittent administration of a cytotoxic or cytostatic agent over thesame total time period.

[0170] A compound according to the invention can be administered to apatient at an oral, intravenous, intramuscular, subcutaneous, orparenteral dosage which can range from about 0.1 to about 200 mg/kg oftotal body weight and the cytotoxic or cytostatic agent can beadministered to a patient at an intravenous, intramuscular,subcutaneous, or parenteral dosage which can range from about 0.1 mg to200 mg/kg of patient body weight.

[0171] This invention further relates to kits comprising separate dosesof the two mentioned chemotherapeutic agents in separate containers. Thecombinations of the invention can also be formed in vivo, e.g., in apatient's body.

[0172] The term “cytotoxic” refers to an agent which can be administeredto kill or eliminate a cancer cell. The term “cytostatic” refers to anagent which can be administered to restrain tumor proliferation ratherthan induce a cytoreduction yielding the elimination of the cancer cellfrom the total viable cell population of the patient. Thechemotherapeutic agents described herein, e.g., irinotecan, vinorelbine,gemcitabine, and paclitaxel are considered cytotoxic agents. Thesecytotoxic and cytostatic agents have gained wide spread use aschemotherapeutics in the treatment of various cancer types and are wellknown in the art. These and other cytotoxic/cytostatic agents can beadministered in the conventional formulations and regimens in which theyare known for use alone.

[0173] Description of Treatment of Hyperproliferative Disorders

[0174] Cancer and hyperproliferative disorders are defined as follows.These disorders include but are not limited to solid tumors, such ascancers of the breast, respiratory tract, brain, reproductive organs,digestive tract, urinary tract, eye, liver, skin, head and neck,thyroid, parathyroid and their distant metastases. Those disorders alsoinclude lymphomas, sarcomas, and leukemias.

[0175] Examples of breast cancer include, but are not limited toinvasive ductal carcinoma, invasive lobular carcinoma, ductal carcinomain situ, and lobular carcinoma in situ.

[0176] Examples of cancers of the respiratory tract include, but are notlimited to small-cell and non-small-cell lung carcinoma, as well asbronchial adenoma and pleuropulmonary blastoma.

[0177] Examples of brain cancers include, but are not limited to brainstem and hypophtalmic glioma, cerebellar and cerebral astrocytoma,medulloblastoma, ependymoma, as well as neuroectodermal and pinealtumor.

[0178] Tumors of the male reproductive organs include, but are notlimited to prostate and testicular cancer.

[0179] Tumors of the female reproductive organs include, but are notlimited to endometrial, cervical, ovarian, vaginal, and vulvar cancer,as well as sarcoma of the uterus.

[0180] Tumors of the digestive tract include, but are not limited toanal, colon, colorectal, esophageal, gallblader, gastric, pancreatic,rectal, small-intestine, and salivary gland cancers.

[0181] Tumors of the urinary tract include, but are not limited tobladder, penile, kidney, renal pelvis, ureter, and urethral cancers.

[0182] Eye cancers include, but are not limited to intraocular melanomaand retinoblastoma.

[0183] Examples of liver cancers include, but are not limited tohepatocellular carcinoma (liver cell carcinomas with or withoutfibrolamellar variant), cholangiocarcinoma (intrahepatic bile ductcarcinoma), and mixed hepatocellular cholangiocarcinoma.

[0184] Skin cancers include, but are not limited to squamous cellcarcinoma, Kaposi's sarcoma, malignant melanoma, Merkel cell skincancer, and non-melanoma skin cancer.

[0185] Head-and-neck cancers include, but are not limited tolaryngeal/hypopharyngeal/nasopharyngeal/oropharyngeal cancer, and lipand oral cavity cancer. Lymphomas include, but are not limited toAIDS-related lymphoma, non-Hodgkin's lymphoma, cutaneous T-celllymphoma, Hodgkin's disease, and lymphoma of the central nervous system.

[0186] Sarcomas include, but are not limited to sarcoma of the softtissue, osteosarcoma, malignant fibrous histiocytoma, lymphosarcoma, andrhabdomyosarcoma. Leukemias include, but are not limited to acutemyeloid leukemia, acute lymphoblastic leukemia, chronic lymphocyticleukemia, chronic myelogenous leukemia, and hairy cell leukemia.

[0187] These disorders have been well characterized in man, but alsoexist with a similar etiology in other mammals, and can be treated bypharmaceutical compositions of the present invention.

[0188] Conditions within a human or other mammal which can be treated byadministering a compound of this invention include tumor growth,retinopathy, including diabetic retinopathy, ischemic retinal-veinocclusion, retinopathy of prematurity and age related maculardegeneration; psoriasis, or bullous disorder associated withsubepidermal blister formation, including bullous pemphigoid, erythemamultiforme, or dermatitis herpetiformis, rheumatoid arthritis,osteoarthritis, septic arthritis, tumor metastasis, periodontal disease,cornal ulceration, proteinuria, coronary thrombosis from atheroscleroticplaque, aneurismal aortic, birth control, dystrophobic epidermolysisbullosa, degenerative cartilage loss following traumatic joint injury,osteopenias mediated by MMP activity, tempero mandibular joint diseaseor demyelating disease of the nervous system.

[0189] Methods of interest treat combinations of conditions such asrheumatic fever, bone resorption, postmenopausal osteoperosis, sepsis,gram negative sepsis, septic shock, endotoxic shock, toxic shocksyndrome, systemic inflammatory response syndrome, inflammatory boweldisease (Crohn's disease and ulcerative colitis), Jarisch-Herxheimerreaction, asthma, adult respiratory distress syndrome, acute pulmonaryfibrotic disease, pulmonary sarcoidosis, allergic respiratory disease,silicosis, coal worker's pneumoconiosis, alveolar injury, hepaticfailure, liver disease during acute inflammation, severe alcoholichepatitis, malaria (Plasmodium falciparum malaria and cerebral malaria),non-insulin-dependent diabetes mellitus (NIDDM), congestive heartfailure, damage following heart disease, atherosclerosis, Alzheimer'sdisease, acute encephalitis, brain injury, multiple sclerosis(demyelation and oligiodendrocyte loss in multiple sclerosis), advancedcancer, lymphoid malignancy, pancreatitis, impaired wound healing ininfection, inflammation and cancer, myclodysplastic syndromes, systemiclupus erythematosus, biliary cirrhosis, bowel necrosis, psoriasis,radiation injury/toxicity following administration of monoclonalantibodies, host-versus-graft reaction (ischemia reperfusion injury andallograft rejections of kidney, liver, heart, and skin), lung allograftrejection (obliterative bronchitis) or complications due to total hipreplacement.

[0190] Also provided is a method for treating an infectious diseaseselected from the group consisting of tuberculosis, Helicobacter pyloriinfection during peptic ulcer disease, Chaga's disease resulting fromTrypanosoma cruzi infection, effects of Shiga-like toxin resulting fromE. coli infection, effects of enterotoxin A resulting fromStaphylococcus infection, meningococcal infection, and infections fromBorrelia burgdorferi, Treponema pallidum, cytomegalovirus, influenzavirus, Theiler's encephalomyelitis virus, and the human immunodeficiencyvirus (HIV).

General Preparative Methods

[0191] The compounds of the invention may be prepared by use of knownchemical reactions and procedures. Nevertheless, the following generalpreparative methods are presented to aid the reader in synthesizing thecompounds of the present invention, with more detailed particularexamples being presented below in the experimental section describingthe working examples.

[0192] All variable groups of these methods are as described in thegeneric description if they are not specifically defined below. When avariable group or substituent with a given symbol is used more than oncein a given structure, it is to be understood that each of these groupsor substituents may be independently varied within the range ofdefinitions for that symbol. It is recognized that compounds of theinvention with each claimed optional functional group cannot be preparedwith each of the below-listed methods. Within the scope of each methodoptional substituents are used which are stable to the reactionconditions, or the functional groups which may participate in thereactions are present in protected form where necessary, and the removalof such protective groups is completed at appropriate stages by methodswell known to those skilled in the art.

[0193] The compounds of this invention can be made according toconventional chemical methods, and/or as disclosed below, from startingmaterials which are either commercially available or producibleaccording to routine, conventional chemical methods. General methods forthe preparation of the compounds are given below, and the preparation ofrelated compounds, is specifically illustrated in Examples.

[0194] Ureas of formula (I) can be prepared by a variety of simplemethods known in the art. General approaches for the formation of thosecompounds can be found in “Advanced Organic Chemistry”, by J. March,John Wiley and Sons, 1985 and in “Comprehensive OrganicTransformations”, by R. C. Larock, VCH Publishers, 1989), which arehereby incorporated by reference.

[0195] More specifically, pyridine-1-oxides, quinoline-1-oxides andisoquinoline-1-oxides and their derivatives can be prepared from thecorresponding pyridines, quinolines, and isoquinolines using oxidationconditions know in the art. Some examples are as follows:

[0196] peracids such as meta chloroperbenzoic acids in chlorinatedsolvents such as dichloromethane, dichloroethane, or chloroform(Markgraf et al., Tetrahedron 1991, 47, 183).

[0197] (Me₃SiO)₂ in the presence of a catalytic amount of perrhenic acidin chlorinated solvents such as dichloromethane (Coperet et al.,Terahedron Lett. 1998, 39, 761)

[0198] Perfluoro-cis-2-butyl-3-propyloxaziridine in several combinationsof halogenated solvents (Amone et al., Tetrahedron 1998, 54, 7831).

[0199] Hypofluoric acid—acetonitrile complex in chloroform (Dayan etal., Synthesis 1999, 1427).

[0200] Oxone, in the presence of a base such as KOH, in water (Robker etal., J. Chem. Res., Synop. 1993, 10, 412).

[0201] Magnesium monoperoxyphthalate, in the presence of glacial aceticacid (Klemm et al., J. Heterocylic Chem. 1990, 6, 1537).

[0202] Hydrogen peroxide, in the presence of water and acetic acid (LinA. J., Org. Prep. Proced. Int. 1991, 23(1), 114).

[0203] Dimethyldioxirane in acetone (Boyd et al., J. Chem. Soc., PerkinTrans. 1991, 9, 2189).

[0204] The starting materials for the above mentioned oxidation are bisaryl ureas, which contain either a pyridine, quinoline, or isoquinolinein one of their side chains. Specific preparations of these ureas arealready described in the patent literature, and can be adapted to thecompounds of the present invention. For example, Miller S. et al,“Inhibition of p38 Kinase using Symmetrical and Unsymmetrical DiphenylUreas” PCT Int. Appl. WO 99 32463, Miller, S et al. “Inhibition of rafKinase using Symmetrical and Unsymmetrical Substituted Diphenyl Ureas”PCT Int. Appl., WO 99 32436, Dumas, J. et al., “Inhibition of p38 KinaseActivity using Substituted Heterocyclic Ureas” PCT Int. App/., WO 9932111, Dumas, J. et al., “Method for the Treatment of Neoplasm byInhibition of raf Kinase using N-Heteroaryl-N′-(hetero)arylureas” PCTInt. Appl., WO 99 32106, Dumas, J. et al., “Inhibition of p38 KinaseActivity using Aryl- and Heteroaryl-Substituted Heterocyclic Ureas” PCTInt. Appl., WO 99 32110, Dumas, J., et al., “Inhibition of raf Kinaseusing Aryl- and Heteroaryl-Substituted Heterocyclic Ureas” PCT Int.Appl, WO 99 32455, Riedl, B., et al., “O-Carboxy Aryl SubstitutedDiphenyl Ureas as raf Kinase Inhibitors” PCT Int. Appl., WO 00 42012,Riedl, B., et al., “O-Carboxy Aryl Substituted Diphenyl Ureas as p38Kinase Inhibitors” PCT Int. Appl., WO 00 41698.

[0205] The following copending U.S. applications are directed to diarylureas that find use in the treatment of raf and/or p38 mediated diseasesand describe the preparation of specific diaryl ureas that areprecursors to the compounds of this invention.

[0206] Ser. No. 08/863,022, filed May 23, 1997;

[0207] Ser. No. 08/996,344, filed Dec. 22, 1997;

[0208] Ser. No. 08/996,343, filed Dec. 22, 1997;

[0209] Ser. No. 08/996,181, filed Dec. 22, 1997;

[0210] Ser. No. 08/995,749, filed Dec. 22, 1997;

[0211] Ser. No. 08/995,750, filed Dec. 22, 1997;

[0212] Ser. No. 08/995,751, filed Dec. 22, 1997;

[0213] Ser. No. 09/083,399, filed May 22, 1998;

[0214] Ser. No. 09/425,228, filed Oct. 22, 1999;

[0215] Ser. No. 09/777,920, filed Feb. 7, 2001.

[0216] Ser. No. 09/838,285, filed Apr. 20, 2001;

[0217] Ser. No. 09/838,286, filed Apr. 20, 2001;

[0218] These applications are incorporated herein by reference.

[0219] The following published PCT applications are directed to diarylureas that find use in the treatment of p38 mediated diseases and alsodescribe the preparation of specific diaryl ureas that are precursors tothe compounds of this invention.

[0220] WO 99/23091;

[0221] WO 00/43384;

[0222] WO 00/55152;

[0223] WO 00/55139 and

[0224] WO 01/36403.

[0225] These applications are also incorporated herein by reference.

[0226] The invention also includes pharmaceutical compositions includinga compound of this invention, and a physiologically acceptable carrier.

[0227] The compounds may be administered orally, topically,parenterally, by inhalation or spray or rectally in dosage unitformulations. The term ‘administration by injection’ includesintravenous, intramuscular, subcutaneous and parenteral injections, aswell as use of infusion techniques. One or more compounds may be presentin association with one or more non-toxic pharmaceutically acceptablecarriers and if desired other active ingredients.

[0228] Compositions intended for oral use may be prepared according toany suitable method known to the art for the manufacture ofpharmaceutical compositions. Such compositions may contain one or moreagents selected from the group consisting of diluents, sweeteningagents, flavoring agents, coloring agents and preserving agents in orderto provide palatable preparations. Tablets contain the active ingredientin admixture with non-toxic pharmaceutically acceptable excipients whichare suitable for the manufacture of tablets. These excipients may be,for example, inert diluents, such as calcium carbonate, sodiumcarbonate, lactose, calcium phosphate or sodium phosphate; granulatingand disintegrating agents, for example, corn starch, or alginic acid;and binding agents, for example magnesium stearate, stearic acid ortalc. The tablets may be uncoated or they may be coated by knowntechniques to delay disintegration and adsorption in thegastrointestinal tract and thereby provide a sustained action over alonger period. For example, a time delay material such as glycerylmonostearate or glyceryl distearate may be employed. These compounds mayalso be prepared in solid, rapidly released form.

[0229] Formulations for oral use may also be presented as hard gelatincapsules wherein the active ingredient is mixed with an inert soliddiluent, for example, calcium carbonate, calcium phosphate or kaolin, oras soft gelatin capsules wherein the active ingredient is mixed withwater or an oil medium, for example peanut oil, liquid paraffin or oliveoil.

[0230] Aqueous suspensions contain the active materials in admixturewith excipients suitable for the manufacture of aqueous suspensions.Such excipients are suspending agents, for example sodiumcarboxymethylcellulose, methylcellulose, hydroxypropyl methylcellulose,sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia;dispersing or wetting agents may be a naturally occurring phosphatide,for example, lecithin, or condensation products or an alkylene oxidewith fatty acids, for example polyoxyethylene stearate, or condensationproducts of ethylene oxide with long chain aliphatic alcohols, forexample heptadecaethylene oxycetanol, or condensation products ofethylene oxide with partial esters derived from fatty acids and hexitolsuch as polyoxyethylene sorbitol monooleate, or condensation products ofethylene oxide with partial esters derived from fatty acids and hexitolanhydrides, for example polyethylene sorbitan monooleate. The aqueoussuspensions may also contain one or more preservatives, for exampleethyl, or n-propyl p-hydroxybenzoate, one or more coloring agents, oneor more flavoring agents, and one or more sweetening agents, such assucrose or saccharin.

[0231] Dispersible powders and granules suitable for preparation of anaqueous suspension by the addition of water provide the activeingredient in admixture with a dispersing or wetting agent, suspendingagent and one or more preservatives. Suitable dispersing or wettingagents and suspending agents are exemplified by those already mentionedabove. Additional excipients, for example, sweetening, flavoring andcoloring agents, may also be present.

[0232] The compounds may also be in the form of non-aqueous liquidformulations, e.g., oily suspensions which may be formulated bysuspending the active ingredients in a vegetable oil, for examplearachis oil, olive oil, sesame oil or peanut oil, or in a mineral oilsuch as liquid paraffin. The oily suspensions may contain a thickeningagent, for example beeswax, hard paraffin or cetyl alcohol. Sweeteningagents such as those set forth above, and flavoring agents may be addedto provide palatable oral preparations. These compositions may bepreserved by the addition of an anti-oxidant such as ascorbic acid.

[0233] Pharmaceutical compositions of the invention may also be in theform of oil-in-water emulsions. The oily phase may be a vegetable oil,for example olive oil or arachis oil, or a mineral oil, for exampleliquid paraffin or mixtures of these. Suitable emulsifying agents may benaturally-occurring gums, for example gum acacia or gum tragacanth,naturally-occurring phosphatides, for example soy bean, lecithin, andesters or partial esters derived from fatty acids and hexitolanhydrides, for example sorbitan monooleate, and condensation productsof the said partial esters with ethylene oxide, for examplepolyoxyethylene sorbitan monooleate. The emulsions may also containsweetening and flavoring agents.

[0234] Syrups and elixirs may be formulated with sweetening agents, forexample glycerol, propylene glycol, sorbitol or sucrose. Suchformulations may also contain a demulcent, a preservative and flavoringand coloring agents.

[0235] The compounds may also be administered in the form ofsuppositories for rectal administration of the drug. These compositionscan be prepared by mixing the drug with a suitable non-irritatingexcipient which is solid at ordinary temperatures but liquid at therectal temperature and will therefore melt in the rectum to release thedrug. Such materials include cocoa butter and polyethylene glycols.

[0236] For all regimens of use disclosed herein for compounds of FormulaI, the daily oral dosage regimen will preferably be from 0.01 to 200mg/kg of total body weight. The daily dosage for administration byinjection, including intravenous, intramuscular, subcutaneous andparenteral injections, and use of infusion techniques will preferably befrom 0.01 to 200 mg/kg of total body weight. The daily rectal dosageregime will preferably be from 0.01 to 200 mg/kg of total body weight.The daily topical dosage regime will preferably be from 0.1 to 200 mgadministered between one to four times daily. The daily inhalationdosage regime will preferably be from 0.01 to 10 mg/kg of total bodyweight. These dosages can be achieved with multiple dosages within a dayor extended dosages (weekly/monthly).

[0237] It will be appreciated by those skilled in the art that theparticular method of administration will depend on a variety of factors,all of which are considered routinely when administering therapeutics.It will also be appreciated by one skilled in the art that the specificdose level for a given patient depends on a variety of factors,including specific activity of the compound administered, age, bodyweight, health, sex, diet, time and route of administration, rate ofexcretion, etc. It will be further appreciated by one skilled in the artthat the optimal course of treatment, i.e., the mode of treatment andthe daily number of doses of a compound of this invention given for adefined number of days, can be ascertained by those skilled in the artusing conventional treatment tests.

[0238] It will be understood, however, that the specific dose level forany particular patient will depend upon a variety of factors, includingthe activity of the specific compound employed, the age, body weight,general health, sex, diet, time of administration, route ofadministration, and rate of excretion, drug combination and the severityof the condition undergoing therapy.

[0239] The compounds can be produced from known compounds (or fromstarting materials which, in turn, can be produced from knowncompounds), e.g., through the general preparative methods shown below.The activity of a given compound to inhibit raf kinase can be routinelyassayed, e.g., according to procedures disclosed below.

[0240] The entire enclosure of all applications, patents andpublications cited above and below are hereby incorporated by reference,including non-provisional application Ser. No. 09/425,228 filed Oct. 22,1999, Ser. No. 09/722,418 filed Nov. 28, 2000 and Ser. No. ______(attorney docket number: Bayer 34 V1), filed Dec. 3, 2001.

[0241] Without further elaboration, it is believed that one skilled inthe art can, using the preceding description, utilize the presentinvention to its fullest extent. The following examples are, therefore,to be construed as merely illustrative and not limitative of theremainder of the disclosure in any way whatsoever.

EXAMPLES

[0242] All reactions are performed in flame-dried or oven-driedglassware under a positive pressure of dry argon or dry nitrogen, andare stirred magnetically unless otherwise indicated. Sensitive liquidsand solutions are transferred via syringe or cannula, and introducedinto reaction vessels through rubber septa. Unless otherwise stated, theterm ‘concentration under reduced pressure’ refers to use of a Buchirotary evaporator at approximately 15 mmHg. Unless otherwise stated, theterm ‘under high vacuum’ refers to a vacuum of 0.4-1.0 mmHg.

[0243] All temperatures are reported uncorrected in degrees Celsius (°C.). Unless otherwise indicated, all parts and percentages are byweight. Commercial grade reagents and solvents are used without furtherpurification.

[0244] Thin-layer chromatography (TLC) is performed using Whatman®pre-coated glass-backed silica gel 60A F-254 250 μm plates.Visualization of plates is effected by one or more of the followingtechniques: (a) ultraviolet illumination, (b) exposure to iodine vapor,(c) immersion of the plate in a 10% solution of phosphomolybdic acid inethanol followed by heating, (d) immersion of the plate in a ceriumsulfate solution followed by heating, and/or (e) immersion of the platein an acidic ethanol solution of 2,4-dinitrophenylhydrazine followed byheating. Column chromatography (flash chromatography) is performed using230-400 mesh EM Science® silica gel.

[0245] Melting points (mp) are determined using a Thomas-Hoover meltingpoint apparatus or a Mettler FP66 automated melting point apparatus andare uncorrected. Fourier transform infrared spectra are obtained using aMattson 4020 Galaxy Series spectrophotometer. Proton (¹H) nuclearmagnetic resonance (NMR) are measured with a General Electric GN-Omega300 (300 MHz) spectrometer with either Me₄Si (60.00) or residualprotonated solvent (CHCl₃ δ7.26; MeOH δ3.30; DMSO δ2.49) as standard.Carbon (¹³C) NMR spectra are measured with a General Electric GN-Omega300 (75 MHz) spectrometer with solvent (CDCl₃ δ77.0; MeOD-d₃; δ49.0;DMSO-d₆ δ39.5) as standard. Low resolution mass spectra (MS) and highresolution mass spectra (HRMS) are either obtained as electron impact(EI) mass spectra or as fast atom bombardment (FAB) mass spectra.Electron impact mass spectra (EI-MS) are obtained with a Hewlett Packard5989A mass spectrometer equipped with a Vacumetrics Desorption ChemicalIonization Probe for sample introduction. The ion source is maintainedat 250° C. Electron impact ionization is performed with electron energyof 70 eV and a trap current of 300 μA. Liquid-cesium secondary ion massspectra (FAB-MS), an updated version of fast atom bombardment isobtained using a Kratos Concept 1-H spectrometer. Chemical ionizationmass spectra (CI-MS) are obtained using a Hewlett Packard MS-Engine(5989A) with methane or ammonia as the reagent gas (1×10⁴ torr to2.5×10⁴ torr). The direct insertion desorption chemical ionization (DCI)probe (Vaccumetrics, Inc.) is ramped from 0-1.5 amps in 10 sec and heldat 10 amps until all traces of the sample disappeared (1-2 min). Spectraare scanned from 50-800 amu at 2 sec per scan. HPLC-electrospray massspectra (HPLC ES-MS) are obtained using a Hewlett-Packard 1100 HPLCequipped with a quaternary pump, a variable wavelength detector, a C-18column, and a Finnigan LCQ ion trap mass spectrometer with electrosprayionization. Spectra are scanned from 120-800 amu using a variable iontime according to the number of ions in the source. Gaschromatography-ion selective mass spectra (GC-MS) is obtained with aHewlett Packard 5890 gas chromatograph equipped with an HP-1 methylsilicone column (0.33 mM coating; 25 m×0.2 mm) and a Hewlett Packard5971 Mass Selective Detector (ionization energy 70 eV). Elementalanalyses are conducted by Robertson Microlit Labs, Madison N.J..

Experimental Synthesis 1

[0246]N-[4-chloro-3-(trifluoromethyl)phenyl]-N′-{4-[2-(N-methylcarbamoyl)-1-oxo-(4-pyridyloxy)]phenyl}urea

[0247] The title compound is not a compound of this invention, and hasbeen distinguished from the compounds of this invention by a proviso.However, its preparation illustrates how other compounds of the presentinvention can be prepared. The oxidation method exemplified herein caneasily be adapted to the compounds of the present invention by thoseskilled in the art.

[0248] To a stirred mixture ofN-[4-chloro-3-(trifluoromethyl)phenyl]-N′-{4-[2-(N-methylcarbamoyl)(4-pyridyloxy)]phenyl}urea (500 mg, 1.08 mmol), in a mixture of anh CH₂Cl₂ (2.2 mL) and anhTHF (2.2 mL) was added 3-chloroperbenzoic acid (77% pure, 1.09 g, 4.86mmol, 4.5 equiv.), and the resulting mixture was heated at 40° C. for 33h. The resulting mixture was concentrated under reduced pressure, andthe crude product was purified by MPLC (Biotage®; gradient from 20%acetone/hexane to 50% acetone/hexane). Recrystallization from EtOAcaffordedN-[4-chloro-3-(trifluoromethyl)phenyl]-N′-{4-[2-(N-methylcarbamoyl)-1-oxo-(4-pyridyloxy)]phenyl}urea as a white solid (293 mg, 57%): mp (uncorrected) 232-234° C.; TLC(50% acetonelhexane) R_(f) 0.13; ¹H-NMR (DMSO-d₆) δ 11.48 (broad s, 1H),9.19 (s, 1H), 8.98 (s, 1H), 8.38 (d, J=5.8 Hz, 1H), 8.10 (d, J=2.5 Hz,1H), 7.64 (dd, J=8.2 Hz, 2.6 Hz, 1H), 7.61 (d, J=8.4 Hz, 1H), 7.57 (d,J=8.7 Hz, 2H), 7.54 (d, J=2.6 Hz, 1H), 7.28 (dd, J=5.7 Hz, 2.5 Hz, 1H),7.18 (d, J=8.8 Hz, 2H), 2.86 (d, J=5.0 Hz, 3H); HPLC EI-MS m/z 481((M+H)⁺). Anal. calcd for C₂₁H₁₆ClFN₄O₄: C, 52.46%; H, 3.33%; N, 11.65%.Found: C, 52.22%; H, 3.39%; N, 11.49%.

Experimental Synthesis 2

[0249]N-[4-chloro-3-(trifluoromethyl)phenyl]-N′-{4-[2-carbamoyl-1-oxo-(4-yridyloxy)]phenyl}urea.

[0250] The title compound is not a compound of this invention. It hasbeen distinguished from the compounds of this invention by a proviso.However, its preparation illustrates how other compounds of the presentinvention can be prepared.

[0251] Step 1: Preparation of 4-chloro-2-pyridinecarboxamide

[0252] To a stirred mixture of methyl 4-chloro-2-pyridinecarboxylatehydrochloride (1.0 g, 4.81 mmol) dissolved in conc. aqueous ammonia (32mL) was added ammonium chloride (96.2 mg, 1.8 mmol, 0.37 equiv.), andthe heterogeneous reaction mixture was stirred at ambient temperaturefor 16 h. The reaction mixture was poured into EtOAc (500 mL) and water(300 mL). The organic layer was washed with water (2×300 mL) and asaturated NaCl solution (1×300 mL), dried (MgSO₄), concentrated in vacuoto give 4-chloro-2-pyridinecarboxamide as a beige solid (604.3 mg,80.3%): TLC (50% EtOAc/hexane) R_(f) 0.20; ¹H-NMR (DMSO-d₆) δ 8.61 (d,J=5.4 Hz, 1H), 8.20 (broad s, 1H), 8.02 (d, J=1.8 Hz, 1H), 7.81 (broads, 1H), 7.76 to 7.73 (m, 1H).

[0253] Step 2: Preparation of 4-(4-aminophenoxy)-2-pyridinecarboxamide

[0254] To 4-aminophenol (418 mg, 3.83 mmol) in anh DMF(7.7 mL) was addedpotassium tert-butoxide (447 mg, 3.98 mmol, 1.04 equiv.) in one portion.The reaction mixture was stirred at room temperature for 2 h, and asolution of 4-chloro-2-pyridinecarboxamide (600 mg, 3.83 mmol, 1.0equiv.) in anh DMF (4 mL) was then added. The reaction mixture wasstirred at 80° C. for 3 days and poured into a mixture of EtOAc and asaturated NaCl solution. The organic layer was sequentially washed witha saturated NH₄Cl solution then a saturated NaCl solution, dried(MgSO₄), and concentrated under reduced pressure. The crude product waspurified using MPLC chromatography (Biotage®; gradient from 100% EtOActo followed by 10% MeOH/50% EtOAc/40% hexane) to give the4-chloro-5-trifluoromethylaniline as a brown solid (510 mg, 58%). ¹H-NMR(DMSO-d₆) δ 8.43 (d, J=5.7 Hz, 1H), 8.07 (br s, 1H), 7.66 (br s, 1H),7.31 (d, J=2.7 Hz, 1H), 7.07 (dd, J=5.7 Hz, 2.7 Hz, 1H), 6.85 (d, J=9.0Hz, 2H), 6.62 (d, J=8.7 Hz, 2H), 5.17 (broad s, 2H); HPLC EI-MS m/z 230((M+H)⁺.

[0255] Step 3: Preparation ofN-[4-chloro-3-(trifluoromethyl)phenyl]-N′-{4-[2-carbamoyl-(4-pyridyloxy)]phenyl}urea

[0256] A mixture of 4-chloro-5-trifluoromethylaniline (451 mg, 2.31mmol, 1.1 equiv.) and 1,1′-carbonyl diimidazole (419 mg, 2.54 mmol, 1.2equiv.) in anh dichloroethane (5.5 mL) was stirred under argon at 65° C.for 16 h. Once cooled to room temperature, a solution of4-(4-aminophenoxy)-2-pyridinecarboxamide (480 mg, 2.09 mmol) in anh THF(4.0 mL) was added, and the reaction mixture was stirred at 60° C. for 4h. The reaction mixture was poured into EtOAc, and the organic layer waswashed with water (2×) and a saturated NaCl solution (1×), dried(MgSO₄), filtered, and evaporated in vacuo. Purification using MPLCchromatography (Biotage®; gradient from 100% EtOAc to 2% MeOH/EtOAc)gaveN-[4-chloro-3-(trifluoromethyl)phenyl]-N′-{4-[2-carbamoyl-(4-pyridyloxy)]phenyl}urea as a white solid (770 mg, 82%): TLC (EtOAc) R_(f) 0.11, 100% ethylacetate ¹H-NMR (DMSO-d₆) δ 9.21 (s, 1H), 8.99 (s, 1H), 8.50 (d, J=5.6Hz, 1H), 8.11 (s, 1H), 8.10 (s, 1H), 7.69 (broad s, 1H), 7.64 (dd, J=8.2Hz, 2.1 Hz, 1H), 7.61 (s, 1H), 7.59 (d, J=8.8 Hz, 2H), 7.39 (d, J=2.5Hz, 1H), 7.15 (d, J=8.9 Hz, 2H), 7.14 (m, 1H); MS LC-MS (MH⁺=451). Anal.calcd for C₂₀H₁₄ClF₃N₄O₃: C, 53.29%; H, 3.13%; N, 12.43%. Found: C,53.33%; H, 3.21%; N, 12.60%.

[0257]N-[4-chloro-3-(trifluoromethyl)phenyl]-N′-{4-[2-carbamoyl-1-oxo-(4-pyridyloxy)]phenyl}urea

[0258]N-[4-chloro-3-(trifluoromethyl)phenyl]-N′-{4-[2-carbamoyl-1-oxo-(4-pyridyloxy)]phenyl}urea (125.6 mg, 51%) was prepared as a white solid fromN-[4-chloro-3-(trifluoromethyl)phenyl]-N′-{4-[2-carbamoyl-(4-pyridyloxy)]phenyl}urea (240.0 mg, 0.53 mmol), in the manner described forN-[4-chloro-3-(trifluoromethyl)phenyl]-N′-{4-[2-(N-methylcarbamoyl)-1-oxo-(4-pyridyloxy)]phenyl}urea: TLC (5% MeOH/CH₂Cl₂) R_(f) 0.17; ¹H-NMR (DMSO-d₆) δ 10.72 (d,J=4.3 Hz, 1H), 9.21 (s, 1H), 8.99 (s, 1H), 8.36 (d, J=7.2 Hz, 1H), 8.31(d, J=4.1 Hz, 1H), 8.10 (d, J=2.3 Hz, 1H), 7.65 (dd, J=8.7 Hz, 2.3 Hz,1H), 7.60 (d, J=8.9 Hz, 1H), 7.57 (d, J=9.0 Hz, 2H), 7.54 (d, J=3.8 Hz,1H), 7.28 (dd, J=7.2 Hz, 3.8 Hz, 1H), 7.18 (d, J=9.0 Hz, 2H); HPLC EI-MSm/z 467 ((M+H)⁺; Anal. calcd for C₂₀H₁₄ClF₃N₄O₄ 0.5H₂O: C, 50.49%; H,3.18%; N, 11.78%. Found. C, 50.69%; H, 2.86%; N, 11.47%.

Biological Examples

[0259] P38 Kinase in vitro Assay:

[0260] The in vitro inhibitory properties of compounds are determinedusing a p38 kinase inhibition assay. P38 activity is detected using anin vitro kinase assay run in 96-well microtiter plates. Recombinanthuman p38 (0.5 μg/mL) is mixed with substrate (myelin basic protein, 5μg/mL) in kinase buffer (25 mM Hepes, 20 mM MgCl₂ and 150 mM NaCl) andcompound. One μCi/well of ³³P-labeled ATP (10 μM) is added to a finalvolume of 100 μL. The reaction is run at 32° C. for 30 min. and stoppedwith a 1M HCl solution. The amount of radioactivity incorporated intothe substrate is determined by trapping the labeled substrate ontonegatively charged glass fiber filter paper using a 1% phosphoric acidsolution and read with a scintillation counter. Negative controlsinclude substrate plus ATP alone.

[0261] LPS Induced TNFα Production in Mice:

[0262] The in vivo inhibitory properties of selected compounds can bedetermined using a murine LPS induced TNFα production in vivo model.BALB/c mice (Charles River Breeding Laboratories; Kingston, N.Y.) ingroups of ten are treated with either vehicle or compound by the routenoted. After one hour, endotoxin (E. coli lipopolysaccharide (LPS) 100μg) is administered intraperitoneally (i.p.). After 90 min, animals areeuthanized by carbon dioxide asphyxiation and plasma is obtained fromindividual animals by cardiac puncture into heparinized tubes. Thesamples are clarified by centrifugation at 12,500×g for 5 min at 4° C.The supernatants are decanted to new tubes, which are stored as neededat −20° C. TNFα levels in sera are measured using a commercial murineTNF ELISA kit (Genzyme).

[0263] The two preceding biological examples can be used to demonstratethat the compounds are inhibiting p38 kinase in vitro and in vivo, andtherefore establishes their utility in the treatment of p38 mediateddiseases, such as inflammation and osteoporosis.

[0264] In Vitro raf Kinase Assay:

[0265] In an in vitro kinase assay, raf is incubated with MEK in 20 mMTris-HCl, pH 8.2 containing 2 mM 2-mercaptoethanol and 100 mM NaCl. Thisprotein solution (20 μL) is mixed with water (5 μL) or with compoundsdiluted with distilled water from 10 mM stock solutions of compoundsdissolved in DMSO. The kinase reaction is initiated by adding 25 μL[y-33P]ATP (1000-3000 dpm/pmol) in 80 mM Tris-HCl, pH 7.5, 120 mM NaCl,1.6 mM DTT, 16 mM MgCl₂. The reaction mixtures are incubated at 32° C.,usually for 22 min. Incorporation of ³³P into protein is assayed byharvesting the reaction onto phosphocellulose mats, washing away freecounts with a 1% phosphoric acid solution and quantitatingphosphorylation by liquid scintillation counting. For high throughputscreening, 10 μM ATP and 0.4 μM MEK are used. In some experiments, thekinase reaction is stopped by adding an equal amount of Laemmli samplebuffer. Samples are boiled 3 min and the proteins resolved byelectrophoresis on 7.5% Laemmli gels. Gels are fixed, dried and exposedto an imaging plate (Fuji). Phosphorylation is analyzed using a FujixBio-Imaging Analyzer System.

[0266] Tumor Cell Proliferation Assay:

[0267] For in vitro growth assay, human tumor cell lines, including butnot limited to HCT116 and DLD-1, containing mutated K-ras genes are usedin standard proliferation assays for anchorage dependent growth onplastic or anchorage independent growth in soft agar. Human tumor celllines are obtained from ATCC (Rockville Md.) and maintained in RPMI with10% heat inactivated fetal bovine serum and 200 mM glutamine. Cellculture media and additives are obtained from Gibco/BRL (Gaithersburg,Md.) except for fetal bovine serum (JRH Biosciences, Lenexa, Kans.). Ina standard proliferation assay for anchorage dependent growth, 3×10³cells are seeded into 96-well tissue culture plates and allowed toattach overnight at 37° C. in a 5% CO₂ incubator. Compounds are titratedin media in dilution series and added to 96 well cell cultures. Cellsare allowed to grow 5 days typically with a feeding of fresh compoundcontaining media on day three. Proliferation is monitored by measuringmetabolic activity with standard XTT colorimetric assay (BoehringerMannheim) measured by standard ELISA plate reader at OD 490/560,harvesting the cells onto glass fiber mats using a cell harvester andmeasuring ³H-thymidine incorporation by liquid scintillant counting.

[0268] For anchorage independent cell growth, cells are plated at 1×10³to 3×10³ in 0.4% Seaplaque agarose in RPMI complete media, overlaying abottom layer containing only 0.64% agar in RPMI complete media in24-well tissue culture plates. Complete media plus dilution series ofcompounds are added to wells and incubated at 37° C. in a 5% CO₂incubator for 10-14 days with repeated feedings of fresh mediacontaining compound at 3-4 day intervals. Colony formation is monitoredand total cell mass, average colony size and number of colonies arequantitated using image capture technology and image analysis software(Image Pro Plus, media Cybernetics).

[0269] The two preceding assays establish that the compounds of FormulaI are active to inhibit raf kinase activity and to inhibit oncogeniccell growth.

[0270] KDR (VEGFR2) Assay:

[0271] The cytosolic kinase domain of KDR kinase is expressed as a 6Hisfusion protein in Sf9 insect cells. The KDR kinase domain fusion proteinis purified over a Ni++ chelating column. Ninety-six well ELISA platesare coated with 5 μg poly(Glu4;Tyr1) (Sigma Chemical Co., St Louis, Mo.)in 100 μl HEPES buffer (20 mM HEPES, pH 7.5, 150 mM NaCl, 0.02%Thimerosal) at 4° overnight. Before use, the plate is washed with HEPES,NaCl buffer and the plates are blocked with 1% BSA, 0.1% Tween 20 inHEPES, NaCl buffer.

[0272] Test compounds are serially diluted in 100% DMSO from 4 mM to0.12 μM in half-log dilutions. These dilutions are further dilutedtwenty fold in H₂O to obtain compound solutions in 5% DMSO. Followingloading of the assay plate with 85 μl of assay buffer (20 mM HEPES, pH7.5, 100 mM KCl, 10 mM MgCl₂, 3 mM MnCl₂, 0.05% glycerol, 0.005% TritonX-100, 1 mM-mercaptoethanol, with or without 3.3 μM ATP), 5 μl of thediluted compounds are added to a final assay volume of 100 μl. Finalconcentrations are between 10 μM, and 0.3 nM in 0.25% DMSO. The assay isinitiated by the addition of 10 μl (30 ng) of KDR kinase domain.

[0273] The assay is incubated with test compound or vehicle alone withgentle agitation at room temperature for 60 minutes. The wells arewashed and phosphotyrosines (PY) are probed with an anti-phosphotyrosine(PY), mAb clone 4G10 (Upstate Biotechnology, Lake Placid, N.Y.).PY/anti-PY complexes are detected with an anti-mouse IgG/HRP conjugate(Amersham International plc, Buckinghamshire, England). Phosphotyrosineis quantitated by incubating with 100 μl 3,3′,5,5′tetramethylbenzidinesolution (Kirkegaard and Perry, TMB Microwell 1 Component peroxidasesubstrate). Color development is arrested by the addition of 100 μl 1%HCl-based stop solution (Kirkegaard and Perry, TMB 1 Component StopSolution).

[0274] Optical densities are determined spectrophotometrically at 450 nmin a 96-well plate reader, SpectraMax 250 (Molecular Devices).Background (no ATP in assay) OD values are subtracted from all ODs andthe percent inhibition is calculated according to the equation:${\% \quad {Inhibition}} = \frac{\left( {{{OD}\left( {{vehicle}\quad {control}} \right)} - {{OD}\left( {{with}\quad {compound}} \right)}} \right) \times 100}{{{OD}\left( {{vehicle}\quad {control}} \right)} - {{OD}\left( {{no}\quad {ATP}\quad {added}} \right)}}$

[0275] The IC₅₀ values are determined with a least squares analysisprogram using compound concentration versus percent inhibition.

[0276] Cell Mechanistic Assay-Inhibition of 3T3 KDR Phosphorylation:

[0277] NIH3T3 cells expressing the full length KDR receptor are grown inDMEM (Life Technologies, Inc., Grand Island, N.Y.) supplemented with 10%newborn calf serum, low glucose, 25 mM/L sodium pyruvate, pyridoxinehydrochloride and 0.2 mg/ml of G418 (Life Technologies Inc., GrandIsland, N.Y.). The cells are maintained in collagen I-coated T75 flasks(Becton Dickinson Labware, Bedford, Mass.) in a humidified 5% CO₂atmosphere at 37° C.

[0278] Fifteen thousand cells are plated into each well of a collagenI-coated 96-well plate in the DMEM growth medium. Six hours later, thecells are washed and the medium is replaced with DMEM without serum.After overnight culture to quiesce the cells, the medium is replaced byDulbecco's phosphate-buffered saline (Life Technologies Inc., GrandIsland, N.Y.) with 0.1% bovine albumin (Sigma Chemical Co., St Louis,Mo.).

[0279] After adding various concentrations (0-300 nM) of test compoundsto the cells in 1% final concentration of DMSO, the cells are incubatedat room temperature for 30 minutes. The cells are then treated with VEGF(30 ng/ml) for 10 minutes at room temperature. Following VEGFstimulation, the buffer is removed and the cells are lysed by additionof 150 μl of extraction buffer (50 mM Tris, pH 7.8, supplemented with10% glycerol, 50 mM BGP, 2 mM EDTA, 10 mM NaF, 0.5 mM NaVO4, and 0.3%TX-100) at 4° C. for 30 minutes.

[0280] To assess receptor phosphorylation, 100 microliters of each celllysate is added to the wells of an ELISA plate precoated with 300 ng ofantibody C20 (Santa Cruz Biotechnology, Inc., Santa Cruz, Calif.).Following a 60-minute incubation, the plate is washed and bound KDR isprobed for phosphotyrosine using an anti-phosphotyrosine mAb clone 4G10(Upstate Biotechnology, Lake Placid, N.Y.). The plate is washed andwells are incubated with anti-mouse IgG/HRP conjugate (AmershamInternational plc, Buckinghamshire, England) for 60 minutes. Wells arewashed and phosphotyrosine is quantitated by addition of 100 μl per wellof 3,3′,5,5′tetramethylbenzidine (Kirkegaard and Perry, TMB Microwell 1Component peroxidase substrate) solution. Color development is arrestedby the addition of 100 μl 1% HCl based stop solution (Kirkegaard andPerry, TMB 1 Component Stop Solution).

[0281] Optical densities (OD) are determined spectrophotometrically at450 nm in a 96-well plate reader (SpectraMax 250, Molecular Devices).Background (no VEGF added) OD values are subtracted from all ODs andpercent inhibition is calculated according to the equation:${\% \quad {Inhibition}} = \frac{\left( {{{OD}\left( {{VEGF}\quad {control}} \right)} - {{OD}\left( {{with}\quad {test}\quad {compound}} \right)}} \right) \times 100}{{{OD}\left( {{VEGF}\quad {control}} \right)} - {{OD}\left( {{no}\quad {VEGF}\quad {added}} \right)}}$

[0282] IC₅₀s are determined on some of the exemplary materials with aleast squares analysis program using compound concentration versuspercent inhibition.

[0283] In Vivo Assay of VEGFR Inhibition: Matrigel® Angiogenesis Model:

[0284] Preparation of Matrigel Plugs and in vivo Phase: Matrigel®(Collaborative Biomedical Products, Bedford, Mass.) is a basementmembrane extract from a murine tumor composed primarily of laminin,collagen IV and heparan sulfate proteoglycan. It is provided as asterile liquid at 4° C., but rapidly forms a solid gel at 37° C.

[0285] Liquid Matrigel at 4° C. is mixed with SK-MEL2 human tumor cellsthat are transfected with a plasmid containing the murine VEGF gene witha selectable marker. Tumor cells are grown in vitro under selection andcells are mixed with cold liquid Matrigel at a ratio of 2×10⁶ per 0.5ml. One half milliliter is implanted subcutaneously near the abdominalmidline using a 25 gauge needle. Test compounds are dosed as solutionsin Ethanol/Cremaphor EL/saline (12.5%:12.5%:75%) at 30, 100, and 300mg/kg po once daily starting on the day of implantation. Mice areeuthanized 12 days post-implantation and the Matrigel pellets areharvested for analysis of hemoglobin content.

[0286] Hemoglobin Assay: the Matrigel pellets are placed in 4 volumes(w/v) of 4° C. Lysis Buffer (20 mM Tris pH 7.5, 1 mM EGTA, 1 mM EDTA, 1%Triton X-100 [EM Science, Gibbstown, N.J.], and complete, EDTA-freeprotease inhibitor cocktail [Mannheim, Germany]), and homogenized at 4°C. Homogenates are incubated on ice for 30 minutes with shaking andcentrifuged at 14K×g for 30 minutes at 4° C. Supernatants aretransferred to chilled microfuge tubes and stored at 4° C. forhemoglobin assay.

[0287] Mouse hemoglobin (Sigma Chemical Co., St. Louis, Mo.) issuspended in autoclaved water (BioWhittaker, Inc, Walkersville, Md.) at5 mg/ml. A standard curve is generated from 500 micrograms/ml to 30micrograms/ml in Lysis Buffer (see above). Standard curve and lysatesamples are added at 5 microliters/well in duplicate to a polystyrene96-well plate. Using the Sigma Plasma Hemoglobin Kit (Sigma ChemicalCo., St. Louis, Mo.), TMB substrate is reconstituted in 50 mls roomtemperature acetic acid solution. One hundred microliters of substrateis added to each well, followed by 100 microliters/well of HydrogenPeroxide Solution at room temperature. The plate is incubated at roomtemperature for 10 minutes.

[0288] Optical densities are determined spectrophotometrically at 600 nmin a 96-well plate reader, SpectraMax 250 Microplate SpectrophotometerSystem (Molecular Devices, Sunnyvale, Calif.). Background Lysis Bufferreadings are subtracted from all wells.

[0289] Total sample hemoglobin content is calculated according to thefollowing equation:

Total Hemoglobin=(Sample Lysate Volume)×(Hemoglobin Concentration)

[0290] The average Total Hemoglobin of Matrigel samples without cells issubtracted from each Total Hemoglobin Matrigel sample with cells.Percent inhibition is calculated according to the following equation:${\% \quad {Inhibition}} = \frac{\left( {{{Average}\quad {Total}\quad {Hemoglobin}\quad {Drug}} - {{Treated}\quad {Tumor}\quad {Lysates}}} \right) \times 100}{\left( {{{Average}\quad {Total}\quad {Hemoglobin}\quad {Non}} - {{Treated}\quad {Tumor}\quad {Lysates}}} \right)}$

[0291] The three preceding assays establish that the compounds ofFormula I are active to inhibit VEGF receptor kinase activity and toinhibit angiogenesis.

[0292] In Vivo Assay of Antitumor Activity:

[0293] An in vivo assay of the inhibitory effect of the compounds ontumors (e.g., solid cancers) mediated by raf kinase can be performed asfollows: CDI nu/nu mice (6-8 weeks old) are injected subcutaneously intothe flank at 1×10⁶ cells with human colon adenocarcinoma cell line. Themice are dosed i.p., i.v. or p.o. at 10, 30, 100, or 300 mg/Kg beginningon approximately day 10, when tumor size is between 50-100 mg. Animalsare dosed for 14 consecutive days; tumor size is monitored with caliperstwice a week. The inhibitory effect of the compounds on p38, raf andVEGFR kinases and therefore on tumor growth (e.g., solid cancers) canfurther be demonstrated in vivo according to the technique of Monia etal. (Nat. Med. 1996, 2, 668-75).

[0294] The preceding examples can be repeated with similar success bysubstituting the generically or specifically described reactants and/oroperating conditions of this invention for those used in the precedingexamples.

[0295] From the foregoing description, one skilled in the art can easilyascertain the essential characteristics of this invention, and withoutdeparting from the spirit and scope thereof, can make various changesand modifications of the invention to adapt it to various conditions andusages.

What is claimed is:
 1. A compound of formula (I) or a salt, prodrug orisolated stereoisomer thereof M-L-B-NH—C(O)—NH-A  I wherein A isselected from the group consisting of: (i) phenyl, optionallysubstituted with 1-3 substituents independently selected from the groupconsisting of R¹, OR¹, NR¹R², S(O)_(q)R₁, SO₂NR¹R², NR¹SO₂R², COR¹,COOR¹, CONR¹R², NR¹C(O)R², halogen, cyano, and nitro; (ii) naphthyl,optionally substituted with 1-3 substituents independently selected fromthe group consisting of R₁, OR₁, NR₁R₂, S(O)_(q)R₁, SO₂NR₁R 2, NR₁SO₂R₂,COR¹, COOR¹, CONR¹R², NR¹C(O)R², halogen, cyano, and nitro; (iii) 5 and6 membered monocyclic heteroaryl, having 1-3 heteroatoms independentlyselected from the group consisting of O, N and S, optionally substitutedwith 1-3 substituents independently selected from the group consistingof R¹, OR¹, NR¹R², S(O)_(q)R¹, SO₂NR¹R², NR¹SO₂R², COR¹, COOR¹, CONR¹R²,NR¹COR², halogen, cyano, and nitro; and (iv) 8-10 membered bicyclicheteroaryl, having 1-6 heteroatoms independently selected from the groupconsisting of O, N and S, optionally substituted with 1-3 substituentsindependently selected from the group consisting of R¹, OR¹, NR¹R²,S(O)_(q)R¹, SO₂NR¹R², NR¹SO₂R², COR¹, COOR¹, CONR¹R², NR¹COR², halogen,cyano, and nitro; B is selected from the group consisting of: (i)phenylene, optionally substituted with 1-3 substituents independentlyselected from the group consisting of C₁-C₅ linear or branched alkyl,C₁-C₅ linear or branched haloalkyl, C₁-C₃ alkoxy, hydroxy, amino, C₁-C₃alkylamino, C₁-C₃ dialkylamino, halogen, cyano, and nitro; (ii)naphthylene, optionally substituted with 1-3 substituents independentlyselected from the group consisting of C₁-C₅ linear or branched alkyl,C₁-C₅ linear or branched haloalkyl, C₁-C₃ alkoxy, hydroxy, amino, C₁-C₃alkylamino, C₁-C₃ dialkylamino, halogen, cyano, and nitro; (iii) 5 and 6membered monocyclic heteroaryl-ene, having 1-3 heteroatoms independentlyselected from the group consisting of O, N and S, optionally substitutedwith 1-3 substituents independently selected from the group consistingof C₁-C₅ linear or branched alkyl, C₁-C₅ linear or branched haloalkyl,C₁-C₃ alkoxy, hydroxy, amino, C₁-C₃ alkylamino, C₁-C₃ dialkylamino,halogen, cyano, and nitro; and (iv) 8-10 membered bicyclicheteroaryl-ene, having 1-6 heteroatoms independently selected from thegroup consisting of O, N and S, optionally substituted with 1-3substituents independently selected from the group consisting of C₁-C₅linear or branched alkyl, C₁-C₅ linear or branched haloalkyl, C₁-C₃alkoxy, hydroxy, amino, C₁-C₃ alkylamino, C₁-C₃ dialkylamino, halogen,cyano, and nitro; L is selected from the group consisting of: (a)—(CH₂)_(m)—O—(CH₂)_(l)—, (b) —(CH₂)_(m)—(CH₂)_(l)—, (c)—(CH₂)_(m)—C(O)—(CH₂)_(l)—, (d) —(CH₂)_(m)—NR^(3a)—(CH₂)_(l)—, (e)—(CH₂)_(m)—NR^(3a)C(O)—(CH₂) _(l)—, (f) —(CH₂)_(m)—S—(CH₂)_(l)—, (g)—(CH₂)_(m)—C(O)NR^(3a)—(CH₂)₁—, (h) —(CH₂)_(m)—CF₂—(CH₂)_(l)—, (i)—(CH₂)_(m)—CCl₂—(CH₂) _(l)—, (j) —(CH₂)_(m)—CHF—(CH₂)_(l)—, (k)—(CH₂)_(m)—CR^(3a)(OH)—(CH₂)_(l)—; (l) —(CH₂)_(m)—C≡C—(CH₂) _(l)—; (m)—(CH₂)_(m)—C═C—(CH₂) _(l)—; (n) a single bond; and(o)—(CH₂)_(m)—CR^(3a)R^(3b)—(CH₂) _(l)—; wherein m and l are integersindependently selected from 0-4; M is selected from the group consistingof: (a) pyridine-1-oxide substituted 1 to 3 times by a substituentselected from the group consisting of —C(O)NR⁴R⁵, —C(NR⁴)R⁵, —C(O)R⁴,—SO₂R⁴, and —SO₂NR⁴R⁵; which is optionally additionally substituted byZ_(r); (b) quinoline-1-oxide, which is optionally substituted by Zn; and(c) isoquinoline-1-oxide, which is optionally substituted by Zn; whereinr is 0-2, n is 0-3, and each Z is independently selected from the groupconsisting of R⁴, halogen, cyano, —CO₂R⁴, —C(O)R⁴, —C(O)NR⁴R⁵, —NO₂,—OR⁴—, —NR⁴R⁵, —NR⁴C(O)OR⁵, —NR⁴C(O)R⁵, —S(O)_(p)R⁴, and —SO₂NR⁴R⁵wherein each R¹, R², R⁴ and R⁵ is independently selected from the groupconsisting of: (a) hydrogen, (b) C₁-C₅ linear, branched, or cyclicalkyl, (c) phenyl, (d) 5-6 membered monocyclic heteroaryl heteroarylhaving 1-4 heteroatoms selected from the group consisting of O, N and Sor 8-10 membered bicyclic heteroaryl having 1-6 heteroatoms selectedfrom the group consisting of O, N and S, (e) C₁-C₃ alkyl-phenyl, (f)C₁-C₃ alkyl heteroaryl having 1-4 heteroatoms selected from the groupconsisting of O, N and S, said heteroaryl including 5-6 memberedmonocyclic and 8-10 membered bicyclic heteroaryl, and (g) up to per-halosubstituted C₁-C₅ linear or branched alkyl; and wherein each R¹, R², R⁴and R⁵, when not hydrogen or perhalo substituted C₁-C₅ linear orbranched alkyl, are optionally substituted with 1-3 substituentsindependently selected from the group consisting of C₁-C₅ linear orbranched alkyl, up to perhalo substituted C₁-C₅ linear or branchedalkyl, C₁-C₃ alkoxy, hydroxy, amino, C₁-C₃ alkylamino, C₁-C₆dialkylamino, halogen, cyano, and nitro; wherein each R^(3a) and R^(3b)is hydrogen or C₁-C₅ linear or branched alkyl; and p and q are integerseach independently selected from 0, 1, or 2 subject to the proviso thatformula I does not include compounds of formula II:

wherein, Y is OR¹ or NHR², Hal is chlorine or bromine, R¹ is H or C₁-C₆alkyl R² is H, OH, CH₃ or CH₂OH, X¹ to X⁷ are each, independently, H, OHor O(CO)C₁-C₄ alkyl.
 2. A compound as in claim 1 wherein A and B offormula I, are each independently: a substituted or unsubstituted phenylgroup, a substituted or unsubstituted a naphthyl group, a substituted orunsubstituted monocyclic heteroaryl group selected from the groupconsisting of 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-triazinyl,4-triazinyl, 1-pyrrolyl, of 2-furyl, 3-furyl 2-thienyl, 4-imidazolyl,5-imidazolyl, 1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl, 5-pyrazolyl,3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-oxazolyl, 4-oxazolyl,5-oxazolyl, 3-oxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl,3-isothiazolyl, 4-isothiazolyl, 5-isothiazolyl, 2-pyridyl, 3-pyridyl,4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 6-pyrimidinyl,1,2,3-triazol-4-yl, 1,2,3-triazol-5-yl, 1,2,4-triazol-1-yl,1,2,3-triazol-3-yl, 1,2,3-triazol-5-yl, 1-tetrazolyl, 5-tetrazolyl,1,2,3-oxadiazol-4-yl, 1,2,3-oxadiazol-5-y 1,1,2,4-oxadiazol-3-yl,1,2,4-oxadiazol-5-yl, 1,3,4-thiadiazol-2-yl, 1,3,4-thiadiazol-5-yl,1,2,4-oxadiazol-3-yl, 1,2,4-oxadiazol-5-yl, 1,3,4-thiadiazol-2-yl,1,3,4-thiadiazol-5-yl, 1,3,4-thiadiazol-3-yl, 1,2,3-thiadiazol-4-yl,1,2,3-thiadiazol-5-yl, 3-pyridazinyl-, 4-pyridazinyl, 2-pyrazinyl and3-pyrazinyl or a substituted or unsubstituted bicyclic heteroaryl groupselected from the group consisting of 2-, 3-, 4-, 5-, 6- and7-benzofuryl, 2-, 3-, 4-, 5-, 6- and 7-benzothienyl, 1-, 2-3-, 4-, 5-,6- and 7-indolyl, 1-, 2-, 3-, 4-, 5-, 6- or 7-isoindolyl, 1-, 2-, 4- and5-benzimidazolyl, 1-, 3-, 4-, 5-, 6- and 7-indazolyl (benzopyrazolyl),2-, 4-, 5-, 6- and 7-benzoxazolyl, 3-, 4-, 5-6- and 7-benzisoxazolyl,1-, 3-, 4-, 5-, 6- and 7-benzothiazolyl, 2-4-, 5-, 6- and7-benzisothiazolyl, 2-, 4-, 5-, 6- and 7-benz-1,3-oxadiazolyl, 2-, 3-,4-, 5-, 6-, 7- and 8-quinolinyl, 1-, 3-, 4-, 5-, 6-, 7-,8-isoquinolinyl, and 2-, 4-, 5-, 6-, 7- and 8-quinazolinyl.
 3. Acompound as in claim 1 wherein A of formula I is a substituted orunsubstituted phenyl group, a substituted or unsubstituted a naphthylgroup, a substituted or unsubstituted monocyclic heteroaryl groupselected from the group consisting of 2-furyl, 3-furyl, 2-thienyl,3-thienyl, 2-triazinyl, 4-triazinyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl,1-imidazolyl 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 1-pyrazolyl,3-pyrazolyl, 4-pyrazolyl, 5-pyrazolyl, 3-isoxazolyl, 4-isoxazolyl,5-isoxazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 3-oxazolyl,2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 3-isothiazolyl, 4-isothiazolyl,5-isothiazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl,4-pyrimidinyl, 5-pyrimidinyl, 6-pyrimidinyl, 1,2,3-triazol-1-yl,1,2,3-triazol-4-yl, 1,2,3-triazol-5-yl, 1,2,4-triazol-1-yl,1,2,3-triazol-3-yl, 1,2,3-triazol-5-yl, 1-tetrazolyl, 5-tetrazolyl,1,2,3-oxadiazol-4-yl, 1,2,3-oxadiazol-5-yl, 1,2,4-oxadiazol-3-yl,1,2,4-oxadiazol-5-yl, 1,3,4-thiadiazol-2-yl, 1,3,4-thiadiazol-5-yl,1,2,4-oxadiazol-3-yl, 1,2,4-oxadiazol-5-yl, 1,3,4-thiadiazol-2-yl,1,3,4-thiadiazol-5-yl, 1,3,4-thiadiazol-3-yl, 1,2,3-thiadiazol-4-yl,1,2,3-thiadiazol-5-yl, 3-pyridazinyl-, 4-pyridazinyl, 2-pyrazinyl and3-pyrazinyl or a substituted or unsubstituted bicyclic heteroaryl groupselected from the group consisting of 2-, 3-, 4-, 5-, 6- and7-benzofuryl, 2-, 3-, 4-, 5-, 6- and 7-benzothienyl, 1-, 2-3-, 4-, 5-,6- and 7-indolyl, 1-, 2-, 4- and 5-benzimidazolyl, 1-, 3-, 4-, 5-, 6-and 7-indazolyl (benzopyrazolyl), 2-, 4-, 5-, 6- and 7-benzoxazolyl, 3-,4-, 5-6- and 7-benzisoxazolyl, 1-, 3-, 4-, 5-, 6- and 7-benzothiazolyl,2-, 4-, 5-, 6- and 7-benzisothiazolyl, 2-, 4-, 5-, 6- and7-benz-1,3-oxadiazolyl, 2-, 3-, 4-, 5-, 6-, 7- and 8-quinolinyl, 1-, 3-,4-, 5-, 6-, 7-, 8-isoquinolinyl, and 2-, 4-, 5-, 6-, 7- and8-quinazolinyl and B of formula I is a substituted or unsubstitutedphenyl group, a substituted or unsubstituted monocyclic heteroaryl groupselected from the group consisting of 2-furyl, 3-furyl, 2-thienyl,3-thienyl, 2-triazinyl, 4-triazinyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl,1-imidazolyl 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 3-isoxazolyl,4-isoxazolyl, 5-isoxazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl,3-oxazoyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 3-isothiazolyl,4-isothiazolyl, 5-isothiazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl,2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 6-pyrimidinyl,1,2,3-triazol-1-yl, 1,2,3-triazol-4-yl, 1,2,3-triazol-5-yl,1,2,4-triazol-1-yl, 1,2,3-triazol-3-yl, 1,2,3-triazol-5-yl,1-tetrazolyl, 5-tetrazolyl, 1,2,3-oxadiazol-4-yl, 1,2,3-oxadiazol-5-yl,1,2,4-oxadiazol-3-yl, 1,2,4-oxadiazol-5-yl, 1,3,4-thiadiazol-2-yl,1,3,4-thiadiazol-5-yl, 1,2,4-oxadiazol-3-yl, 1,2,4-oxadiazol-5-yl,1,3,4-thiadiazol-2-yl, 1,3,4-thiadiazol-5-yl, 1,3,4-thiadiazol-3-yl,1,2,3-thiadiazol-4-yl, 1,2,3-thiadiazol-5-yl, 3-pyridazinyl-,4-pyridazinyl, 2-pyrazinyl and 3-pyrazinyl or a substituted orunsubstituted bicyclic heteroaryl group selected from the groupconsisting of 2-, 3-, 4-, 5-, 6- and 7-benzofuryl, 2-, 3-, 4-, 5-, 6-and 7-benzothienyl, 1-, 2-3-, 4-, 5-, 6- and 7-indolyl, 1-, 2-, 4- and5-benzimidazolyl, 1-, 3-, 4-, 5-, 6- and 7-indazolyl (benzopyrazolyl),2-, 4-, 5-, 6- and 7-benzoxazolyl, 3-, 4-, 5-6- and 7-benzisoxazolyl,1-, 3-, 4-, 5-, 6- and 7-benzothiazolyl, 2-, 4-, 5-, 6- and7-benzisothiazolyl, 2-, 4-, 5-, 6- and 7-benz-1,3-oxadiazolyl, 2-, 3-,4-, 5-, 6-, 7- and 8-quinolinyl, 1-, 3-, 4-, 5-, 6-, 7-,8-isoquinolinyl, and 2-, 4-, 5-, 6-, 7- and 8-quinazolinyl.
 4. Acompound as in claim 1 wherein A of formula I is a substituted orunsubstituted group selected from the group consisting of phenyl,naphthyl, furyl, isoindolyl, oxadiazolyl, oxazolyl, isooxazolyl,indolyl, indazolyl, benzothiazolyl, benzimidazolyl, benzoxazolyl,pyrazolyl, pyridinyl, pyrimidinyl, pyrrolyl, quinolinyl, isoquinolinyl,tetrazolyl, thiadiazolyl, thiazolyl and thienyl, B of formula I is asubstituted or unsubstituted group selected from the group consisting ofphenylene, naphthylene, thienylene, furylene, pyridine-ene,quinoline-ene, isoquinoline-ene and indole-ene, L is selected from thegroup consisting of —CH₂O—, —OCH₂—, —O—, a single bond, —CH₂—, —NH—,—N(CH₃)—, —N(CH₃)CH₂—, —NC₂H₄—, —C(O)—, —NHCH₂—, —N(CH₃)C(O)—, —NHC(O)—,—CH₂N(CH₃)—, —C(O)NH—, —CH₂S—, —SCH₂—, —S—, —C(O)NCH₃—, —CH₂C(O)N(CH₃)—,—C(O)N(CH₃)CH₂—, —CF₂—, —CCl₂—, —CHF— and —CH(OH)—, and M is defined asin claim
 1. 5. A compound as in claim 1 wherein A of formula I is asubstituted or unsubstituted group selected from the group consisting ofphenyl, naphthyl, furyl, isoindolyl, oxadiazolyl, oxazolyl, isoxazolyl,indolyl, indazolyl, benzothiazolyl, benzimidazolyl, benzoxazolyl,pyrazolyl, pyridinyl, pyrimidinyl, pyrrolyl, quinolinyl, isoquinolinyl,tetrazolyl, thiadiazolyl, thiazolyl and thienyl, B of formula I is asubstituted or unsubstituted group selected from the group consisting ofphenylene, thienylene, furylene, pyridine-ene, quinoline-ene,isoquinoline-ene and indole-ene, L is selected from the group consistingof —CH₂O—, —OCH₂—, —O—, a single bond, —CH₂—, —NH—, —N(CH₃)—,—N(CH₃)CH₂—, —NC₂H₄—, —C(O)—, —NHCH₂—, —N(CH₃)C(O)—, —NHC(O)—,—CH₂N(CH₃)—, —C(O)NH—, —CH₂S—, —SCH₂—, —S—, —C(O)NCH₃—, —CH₂C(O)N(CH₃)—,—C(O)N(CH₃)CH₂—, —CF₂—, —CCl₂—, —CHF— and —CH(OH)—, and M is defined asin claim
 1. 6. A compound as in claim 4 wherein A of formula I is asubstituted group and the substituents are selected from the groupconsisting of methyl, trifluoromethyl, ethyl, n-propyl, n-butyl,n-pentyl, i-propyl, t-butyl, methylethyl, methylpropyl, cyclopropyl,cyclobutyl, cyclopentyl, methoxy, ethoxy, propoxy, butyoxy, pentoxy,methyl sulfonyl, trifluoromethyl sulfonyl, Cl, Br, F, cyano, nitro,hydroxy, amino, methylamino, dimethylamino, ethylamino and diethylamino.7. A compound as in claim 1 wherein A of formula I is a substituted orunsubstituted group selected from the group consisting of phenyl,pyridinyl, pyrimidinyl, pyrazolyl, quinolinyl, isoquinolinyl,isoindolyl, pyrrolyl, indazolyl, thienyl, furyl and isoxazolyl and B offormula I is a substituted or unsubstituted group selected from thegroup consisting of phenylene, naphthylene, thienylene, furylene,pyridine-ene, quinoline-ene, isoquinoline-ene and indole-ene.
 8. Acompound as in claim 1 wherein A of formula I is a substituted orunsubstituted group selected from the group consisting of phenyl,pyridinyl, pyrimidinyl, pyrazolyl, quinolinyl, isoquinolinyl,isoindolyl, pyrrolyl, indazolyl, thienyl, furyl and isoxazolyl and B offormula I is a substituted or unsubstituted group selected from thegroup consisting of phenylene, thienylene, furylene, pyridine-ene,isoquinoline-ene and indole-ene.
 9. A compound as in claim 1 wherein Aof formula I is a substituted or unsubstituted group selected from thegroup consisting of phenyl, pyridinyl, pyrimidinyl, pyrazolyl,quinolinyl, isoquinolinyl, isoindolyl, pyrrolyl, indazolyl, thienyl,furyl and isoxazolyl and B of formula I is a substituted orunsubstituted group selected from the group consisting of phenylene andpyridine-ene.
 10. A compound as in claim 7 wherein A of formula I is asubstituted group and the substituents are selected from the groupconsisting of: NH(C₁-C₅ alkyl, phenyl or pyridinyl); N(C₁-C₅alkyl)(C₁-C₅ alkyl, phenyl or pyridinyl); S(O)₂ (C₁-C₅ alkyl);SO₂NH(C₁-C₅ alkyl); SO₂N(C₁-C₅ alkyl)(C₁-C₅ alkyl); NHSO₂(C₁-C₅ alkyl);N(C₁-C₃ alkyl) SO₂(C₁-C₅ alkyl); CO(C₁-C₆ alkyl, phenyl or pyridinyl);COO(C₁-C₆ alkyl, phenyl or pyridinyl); COOH; CONH₂; CONH(C₁-C₆ alkyl,phenyl or pyridinyl); CON(C₁-C₆ alkyl, phenyl or pyridinyl); NHCO(C₁-C₅alkyl, phenyl or pyridinyl) and N(C₁-C₅ alkyl)CO(C₁-C₅ alkyl).
 11. Acompound of formula I of claim 1 wherein in A, and B are one of thefollowing combinations and M is as defined in claim 1: A=phenyl,B=phenylene, A=phenyl, B=pyridinyl-ene, A=phenyl, B=isoquinolinyl-ene,A=pyridinyl, B=phenylene, A=pyridinyl, B=pyridinyl-ene, A=pyridinyl,B=isoquinolinyl-ene, A=naphthyl, B=phenylene, A=naphthyl,B=pyridinyl-ene, A=naphthyl, B=isoquinolinyl-ene, A=isoquinolinyl,B=phenylene, A=isoquinolinyl, B=pyridinyl-ene, A=isoquinolinyl,B=isoquinolinyl-ene, A=quinolinyl, B=phenylene, A=quinolinyl,B=pyridinyl-ene, A=quinolinyl, B=isoquinolinyl-ene, A=pyrazolyl,B=phenylene, A=pyrazolyl, B=pyridinyl-ene, A=pyrazolyl,B=isoquinolinyl-ene, A=isoxazolyl, B=phenylene, A=isoxazolyl,B=pyridinyl-ene, A=isoxazolyl, B=isoquinolinyl-ene. A=indazolyl,B=phenylene, A=indazolyl, B=pyridinyl-ene, and A=indazolyl,B=isoquinolinyl-ene.
 12. A pharmaceutical composition comprising a) oneor more compounds of formula I of claim 1, or a isolated stereoisomer, apharmaceutically acceptable salt, or a prodrug of a compound of formula(I) and b) at least one pharmaceutically acceptable carrier.
 13. Apharmaceutical composition comprising a) one or more compounds offormula I of claim 1, or a salt, prodrug or isolated stereoisomer of acompound of formula I, b) at least one other cytotoxic or cytostaticchemotherapeutic agent, wherein the amounts of a) and b) are jointlyeffective for treating a cancer, and c) at least one pharmaceuticallyacceptable carrier.
 14. A method for the treatment of raf-mediateddisease states in humans and/or other mammals, which comprisesadministering a compound of formula I or a salt, prodrug or isolatedstereoisomer thereof to a human or other mammal in need thereof.
 15. Amethod for the treatment of p38-mediated disease states in humans and/orother mammals, which comprises administering a compound of formula I ofclaim 1 or a salt, prodrug or isolated stereoisomer thereof to a humanor other mammal in need thereof.
 16. A method for the treatment ofVEGF-mediated disease states in humans and/or other mammals, whichcomprises administering a compound of formula I of claim 1 or a salt,prodrug or isolated stereoisomer thereof to a human or other mammal inneed thereof.
 17. A method as in claim 16 wherein the disease mediatedby the VEGF-induced signal transduction pathway that is treated ischaracterized by abnormal angiogenesis or hyperpermiability processes.18. A method as in claim 16 wherein the disease that is treated is oneor more of the following conditions in humans and/or other mammals:tumor growth, retinopathy, ischemic retinal-vein occlusion, retinopathyof prematurity, age related macular degeneration; rheumatoid arthritis,psoriasis, a bullous disorder associated with subepidermal blisterformation, including bullous pemphigoid, erythema multiforme, ordermatitis herpetiformis.
 19. A method as in claim 16 wherein thedisease that-is treated is one or more of the following conditions inhumans and/or other mammals: tumor growth, retinopathy, diabeticretinopathy, ischemic retinal-vein occlusion, retinopathy ofprematurity, age related macular degeneration; rheumatoid arthritis,psoriasis, bullous disorder associated with subepidermal blisterformation, bullous pemphigoid, erythema multiforme, and dermatitisherpetiformis, in combination with an infectious disease selected fromthe group consisting of: tuberculosis, Helicobacter pylori infectionduring peptic ulcer disease, Chaga's disease resulting from Trypanosomacruzi infection, effects of Shiga-like toxin resulting from E. coliinfection, effects of enterotoxin A resulting from Staphylococcusinfection, meningococcal infection, and infections from Borreliaburgdorferi, Treponema pallidum, cytomegalovirus, influenza virus,Theiler's encephalomyelitis virus, and the human immunodeficiency virus(HIV).
 20. A method for the treatment of hyper-proliferative,inflammatory and angiogenesis disorders and osteoporosis in humansand/or other mammals which comprises administering a compound of formulaI of claim 1 or a salt, prodrug or isolated stereoisomer thereof to ahuman or other mammal in need thereof.
 21. A method for the treatment orprevention of cancer in humans and other mammals which comprisesadministering a compound of formula I of claim 1 or a salt, prodrug orisolated stereoisomer thereof to a human or other mammal in needthereof.
 22. A method as in claim 21 wherein a compound of formula I ofclaim 1, or a salt, prodrug or isolated stereoisomer thereof, isadministered in combination with an additional anti-proliferative agentin the same formulation or in separate formulations.
 23. A method as inclaim 22 wherein the additional anti-proliferative agent is a cytotoxicagent selected from the group consisting of asparaginase, bleomycin,carboplatin, carmustine, chlorambucil, cisplatin, colaspase,cyclophosphamide, cytarabine, dacarbazine, dactinomycin, daunorubicin,doxorubicin (adriamycine), epirubicin, epothilone, etoposide,5-fluorouracil, hexamethylmelamine, hydroxyurea, ifosfamide, irinotecan,leucovorin, lomustine, mechlorethamine, 6-mercaptopurine, mesna,methotrexate, mitomycin C, mitoxantrone, prednisolone, prednisone,procarbazine, raloxifen, streptozocin, tamoxifen, thioguanine,topotecan, vinblastine, vincristine, vindesine, oxaliplatin,gemcitabone, gefinitib, taxotere, ara A, ara C, herceptin, BCNU, CCNU,DTIC, and actinomycin D.
 24. A method as in claim 23 wherein theadditional anti-proliferative agent is selected from the groupconsisting aminoglutethimide, L-asparaginase, azathioprine,5-azacytidine cladribine, busulfan, diethylstilbestrol, 2′,2′-difluorodeoxycytidine, docetaxel, erythrohydroxynonyladenine, ethinylestradiol, 5-fluorodeoxyuridine, 5-fluorodeoxyuridine monophosphate,fludarabine phosphate, fluoxymesterone, flutamide, hydroxyprogesteronecaproate, idarubicin, interferon, medroxyprogesterone acetate, megestrolacetate, melphalan, mitotane, paclitaxel, pentostatin,N-phosphonoacetyl-L-aspartate (PALA), plicamycin, semustine, teniposide,testosterone propionate, thiotepa, trimethylmelamine, uridine, andvinorelbine.
 25. A method as in claim 21 for treating cancers notmediated by raf kinase.
 26. A method as in claim 21 wherein a compoundof formula I of claim 1 or a salt, prodrug or isolated stereoisomerthereof is administered in combination with at least one cytotoxic orcytostatic chemotherapeutic agent in the same formulation or in separateformulations.
 27. A method as in claim 26 wherein the cytotoxic orcytostatic chemotherapeutic agent is selected from the group consistingof DNA topoisomerase I and II inhibitors, DNA intercalators, alkylatingagents, microtubule disruptors, hormone and growth factor receptoragonists or antagonists, other kinase inhibitors and anti-metabolites.28. A method as in claim 21 wherein a compound of formula I of claim 1,or a salt, prodrug or isolated stereoisomer thereof, is administeredsimultaneously with a cytotoxic or cytostatic chemotherapeutic agent toa patient with a cancer, in the same formulation.
 29. A kit comprising aseparate dose of a compound of formula I of claim 1, or a salt, prodrugor isolated stereoisomer thereof, and a separate dose of a cytotoxic orcytostatic chemotherapeutic agent in separate containers.
 30. A methodfor the treatment of a condition in humans and/or other mammals whichcomprises administering a compound of formula I of claim 1 or a salt,prodrug or isolated stereoisomer thereof to a human or other mammal withsaid condition, wherein said condition is selected from the groupconsisting of retinopathy, ischemic retinal-vein occlusion, age relatedmacular degeneration; psoriasis, bullous disorder associated withsubepidermal blister formation, erythema multiforme, dermatitisherpetiformis, rheumatoid arthritis, osteoarthritis, septic arthritis,tumor metastasis, periodontal disease, cornal ulceration, proteinuriaand coronary thrombosis from atherosclerotic plaque, aneurismal aortic,birth control, dystrophobic epidermolysis bullosa, degenerativecartilage loss following traumatic joint injury, osteopenias mediated byMMP activity, tempero mandibular joint disease or demyelating disease ofthe nervous system.
 31. A method for the treatment of a condition inhumans and/or other mammals which comprises administering a compound offormula I of claim 1 or a salt, prodrug or isolated stereoisomer thereofto a human or other mammal with said condition, wherein said conditionis selected from the group consisting of rheumatic fever, boneresorption, postmenopausal osteoporosis, sepsis, gram negative sepsis,septic shock, endotoxic shock, toxic shock syndrome, systemicinflammatory response syndrome, inflammatory bowel disease (Crohn'sdisease and ulcerative colitis), Jarisch-Herxheimer reaction, asthma,adult respiratory distress syndrome, acute pulmonary fibrotic disease,pulmonary sarcoidosis, allergic respiratory disease, silicosis, coalworker's pneumoconiosis, alveolar injury, hepatic failure, liver diseaseduring acute inflammation, severe alcoholic hepatitis, malaria(Plasmodium falciparum malaria and cerebral malaria),non-insulin-dependent diabetes mellitus (NIDDM), congestive heartfailure, damage following heart disease, atherosclerosis, Alzheimer'sdisease, acute encephalitis, brain injury, multiple sclerosis(demyelation and oligiodendrocyte loss in multiple sclerosis), advancedcancer, lymphoid malignancy, pancreatitis, impaired wound healing ininfection, inflammation and cancer, myelodysplastic syndromes, systemiclupus erythematosus, biliary cirrhosis, bowel necrosis, psoriasis,radiation injury/toxicity following administration of monoclonalantibodies, host-versus-graft reaction (ischemia reperfusion injury andallograft rejections of kidney, liver, heart, and skin), lung allograftrejection (obliterative bronchitis) or complications due to total hipreplacement.
 32. A method of treating or preventing ahyper-proliferative disorder in humans and/or other mammals comprisingadministering an effective amount of a compound of formula I of claim 1to said human or mammal.
 33. A method as in claim 32 wherein the diseasetreated is selected from the group consisting of tuberculosis,Helicobacter pylori infection during peptic ulcer disease, Chaga'sdisease resulting from Trypanosoma cruzi infection, effects ofShiga-like toxin resulting from E. coli infection, effects ofenterotoxin A resulting from Staphylococcus infection, meningococcalinfection, and infections from Borrelia burgdorferi, Treponema pallidum,cytomegalovirus, influenza virus, Theiler's encephalomyelitis virus, andthe human immunodeficiency virus (HIV).
 34. A method of treating orpreventing osteoporosis, inflammation, and angiogenesis disorders, withthe exclusion of raf-mediated cancer, in a human and/or other mammal byadministering an effective amount of a compound of claim 1 to saidmammal.
 35. A method of preparing compounds of claim 1 which comprisesthe step oxidizing the nitrogen of pyridyl ring M to form thecorresponding pyridine-1-oxide.